Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands

ABSTRACT

Compounds provided herein are novel substituted pyrazinones, pyridines and pyrimidines of Formula (I) and (II): 
                         
Such compounds are particularly useful as CRF receptor ligands, and hence, in the treatment of various neurologically-related disorders such as affective disorder, anxiety and depression.

This application is a divisional of U.S. application Ser. No. 10/145,440, filed May 14, 2002, now U.S. Pat. No. 7,205,306, which claims the benefit of U.S. Provisional Application No. 60/290,706 filed May 14, 2001, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to compounds which are novel substituted pyrazinones, pyridines and pyrimidines; to pharmaceutical compositions thereof, and to the use of such compounds as CRF receptor ligands in the treatment of various CRF-related disorders.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].

Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p 221 (1990)].

It has been further postulated that CRF has a role in cardiovascular or heart-related diseases as well as gastrointestinal disorders arising from stress such as hypertension, tachycardia and congestive heart failure, stroke, irritable bowel syndrome post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see E. D. DeSouza, C. B. Nemeroff, Editors; Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p 221 (1990) and C. Maillot, M. Million, J. Y. Wei, A. Gauthier, Y. Tache, Gastroenterology, 119, 1569-1579 (2000)].

Over-expression or under-expression of CRF has been proposed as an underlying cause for several medical disorders. Such treatable disorders include, for example and without limitation: affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see J. R. McCarthy, S. C. Heinrichs and D. E. Grigoriadis, Cur. Pharm. Res., 5, 289-315 (1999); P. J. Gilligan, D. W. Robertson and R. Zaczek, J. Medicinal Chem., 43, 1641-1660 (2000), G. P. Chrousos, Int. J. Obesity, 24, Suppl. 2, S50-S55 (2000); E. Webster, D. J. Torpy, I. J. Elenkov, G. P. Chrousos, Ann. N.Y. Acad. Sci., 840, 21-32 (1998); D. J. Newport and C. B. Nemeroff, Curr. Opin. Neurobiology, 10, 211-218 (2000); G. Mastorakos and I. Ilias, Ann. N.Y. Acad. Sci., 900, 95-106 (2000); M. J. Owens and C. B. Nemeroff, Expert Opin. Invest. Drugs, 8, 1849-1858 (1999); G. F. Koob, Ann. N.Y. Acad. Sci., 909, 170-185 (2000)].

Lastly, studies have demonstrated that CRF-1 antagonists are may be useful as hair growth stimulators. PCT publication WO2002/19975 discloses cell culture assays for the use of CRF antagonists in stimulating KBM-2 cell production. Thus, CRF antagonists may be useful in treatment of hair loss.

The following publications each describe CRF antagonist compounds; however, none disclose the compounds provided herein: WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308; WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454; and WO00/01675. Even with the current development efforts of CRF antagonist compounds, it is desirable to develop additional CRF receptor ligands in the treatment of various CRF-related disorders.

SUMMARY OF THE INVENTION

This invention is a class of novel compounds which are CRF receptor ligands and which can be represented by Formula (I) and (II):

or a pharmaceutically acceptable salt form thereof, wherein:

-   X is N or CR¹; -   provided that when X is N, R¹ can not be either —NR⁹R¹⁰ or —NR⁹COR⁹; -   W is ═O, ═S, —H or (—H, —H); -   Y is —C(═O)—, —C(R^(Y))₂—, —C(R^(Y))₂CH₂—, —OCH₂—, —SO_(n)CH₂—, —N═,     —NR^(Y)—, —O—, or —CH═; -   R^(Y) is independently, at each occurrence, selected from H, methyl,     ethyl, and C₁-C₂ haloalkyl; -   B is R³, NHR³, NR³R¹, OR³, or SO_(n)R³; -   R¹ is independently, at each occurrence, selected from H, halogen,     —CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, and C₄-C₈ cycloalkylalkyl;     -   wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, or C₄-C₈ cycloalkylalkyl is each optionally         substituted with halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰,         —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or —S(O)_(n)R¹²; -   R² is H, halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, NR⁹COR⁹, —COR¹⁰,     —OR¹⁰, SH, —S(O)_(n)R¹², C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₈     cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₈         cycloalkylalkyl is optionally substituted with halogen, —CN,         C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or         —S(O)_(n)R¹²; -   R^(2a) is H, F, Cl, Br, —CN, —OH, methyl, ethyl, propyl,     cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, C₁-C₃ alkoxy,     cyclopropyloxy-, —OCF₃, —CF₃, —CO₂CH₃, —CO₂CH₂CH₃, —C(O)CH₃,     —C(O)CH₂CH₃, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —C(O)NH₂, —C(O)N(H)CH₃,     —C(O)N(H)CH₂CH₃, —C(O)N(CH₃)₂, —C(O)N(CH₃)CH₂CH₃, —C(O)N(CH₂CH₃)₂,     —S(O)₂N(CH₃)₂, —S(O)₂N(CH₃)CH₂CH₃, —S(O)₂N(CH₂CH₃)₂, —S(O)₂CH₃,     —S(O)₂CH₂CH₃, —NH₂, —N(H)CH₃, —N(H)CH₂CH₃, —N(CH₃)₂, —N(CH₃)CH₂CH₃,     —N(CH₂CH₃)₂, or —N(H)CF₃; -   R³ is C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀     cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₈ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀         alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano,         —OR⁷, SH, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂, —NR⁷CONR⁶R⁷,         —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and         heterocyclyl; -   alternatively, R³ is —OR^(3a), —NR^(3a)R^(3b), —NHR^(3a),     —SO_(n)R^(3a), —SO₂NHR^(3a), —SO₂NR^(3a)R^(3b), —COR^(3a),     —CONHR^(3a), or CONR^(3a)R^(3b); -   R^(3a) and R^(3b) are independently selected from C₁-C₁₀ alkyl,     C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀ cycloalkenyl, and C₆-C₁₀     cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl may be replaced with O, S         or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, and C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1 to 3 substituents independently selected at         each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀ alkynyl,         C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano, —OR⁷, —SH,         —S(O)_(n)R¹¹, —COR⁶, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂,         —NR⁷CONR⁶R⁷, —NR⁷CO₂R⁸, —NR⁶R⁷, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and heterocyclyl; -   R⁴ is independently selected in each occurrence from —H, —OR¹⁰,     —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², —S(O)₂NR⁹R¹⁰,     —NO₂, halogen, C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆     cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl and heteroaryl;     -   wherein C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ is CR⁵ or N; -   A² is CR⁵ or N; -   R⁵ is independently selected at each occurrence from —H, C₁-C₁₀     alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₂-C₁₀ alkenyl, C₂-C₁₀     alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, —NO₂, halogen,     —CN, —NR⁶R⁷, —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹,     —CO₂R⁸, —S(O)₂NR⁹R¹⁰, and —S(O)_(n)R¹¹;     -   wherein C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, and —S(O)_(n)R¹¹; -   alternatively, two R⁵ groups on adjacent atoms can form a 5-7     membered fused ring, partially saturated or unsaturated, optionally     containing 1-2-O— or —SO_(n)— or 1-3 N heteroatoms provided the ring     does not contain any S—S, O—O, S—O or N—S bonds;     -   said 5-7 membered fused ring optionally substituted with C₁-C₄         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₈         cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,         NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO₂R⁸, —CO(NOR⁹)R⁷, or         —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₄     haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   alternatively NR⁶R⁷ is piperidine, pyrrolidine, piperazine,     N-methylpiperazine, morpholine or thiomorpholine; -   R⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R¹¹ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl,     aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl), or —NR⁶R⁷; -   R¹² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁-C₆     alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³²,     —COR³², —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,     thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,     benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or     indazolyl, each optionally substituted with 1 to 3 substituents     independently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³², —COR³²,     —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 3 substituents independently     selected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄     haloalkyl, cyano, —OR³⁰, SH, —S(O)_(n)R³², —COR³², —CO₂R³²,     —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰, —NR²⁹CO₂R³²,     —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   R²⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, phenyl, or     phenyl(C₁-C₄ alkyl)-; -   R²⁹ and R³⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R³² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; and -   n is 0, 1, or 2.

DETAILED DESCRIPTION OF THE INVENTION

This invention is a class of novel compounds which are CRF receptor ligands and which can be represented by Formula (I-a) and (II):

or a pharmaceutically acceptable salt form thereof, wherein:

-   X is N or CR¹; -   provided that when X is N, R¹ can not be either —NR⁹R¹⁰ or —NR⁹COR⁹; -   W is O, S, H or (—H, —H); -   Y is CO, CH₂, CH₂CH₂, OCH₂, SO_(n)CH₂, N, NH, NCH₃, O, or CH; -   B is R³, NHR³, NR³R¹, OR³, or SO_(n)R³; -   R¹ is independently, at each occurrence, selected from H, halogen,     —CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, and C₄-C₈ cycloalkylalkyl;     -   wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, or C₄-C₈ cycloalkylalkyl is each optionally         substituted with halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰,         —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or —S(O)_(n)R¹²; -   R² is H, halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, NR⁹COR⁹, —COR¹⁰,     —OR¹⁰, SH, —S(O)_(n)R¹², C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₈     cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₈         cycloalkylalkyl is optionally substituted with halogen, —CN,         C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or         —S(O)_(n)R¹²; -   R³ is C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀     cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₈ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀         alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano,         —OR⁷, SH, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂, —NR⁷CONR⁶R⁷,         —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and         heterocyclyl; -   alternatively, R³ is —OR^(3a), —NR^(3a)R^(3b), —NHR^(3a),     —SO_(n)R^(3a), —SO₂NHR^(3a), —SO₂NR^(3a)R^(3b), —COR^(3a),     —CONHR^(3a), or CONR^(3a)R^(3b); -   R^(3a) and R^(3b) are independently selected from C₁-C₁₀ alkyl,     C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀ cycloalkenyl, and C₆-C₁₀     cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl may be replaced with O, S         or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, and C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1 to 3 substituents independently selected at         each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀ alkynyl,         C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano, —OR⁷, —SH,         —S(O)_(n)R¹¹, —COR⁶, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂,         —NR⁷CONR⁶R⁷, —NR⁷CO₂R⁸, —NR⁶R⁷, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and heterocyclyl; -   R⁴ is independently selected in each occurrence from —H, —OR¹⁰,     —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², halogen, C₁-C₆     alkyl, C₁-C₄ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₆     alkenyl, C₂-C₆ alkynyl, aryl and heteroaryl;     -   wherein C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ is CR⁵ or N; -   A² is CR⁵ or N; -   R⁵ is independently at each occurrence —H, C₁-C₁₀ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,     —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹, —CO₂R⁸, or     —S(O)_(n)R¹¹;     -   wherein C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, or —S(O)_(n)R¹¹; -   alternatively, two R⁵ groups on adjacent atoms can form a 5-7     membered fused ring, partially saturated or unsaturated, optionally     containing 1-2-O— or —SO_(n)— or 1-3 N heteroatoms provided the ring     does not contain any S—S, O—O, S—O or N—S bonds;     -   said 5-7 membered fused ring optionally substituted with C₁-C₄         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₈         cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,         NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO₂R⁸, —CO(NOR⁹)R⁷, or         —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₄     haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   alternatively NR⁶R⁷ is piperidine, pyrrolidine, piperazine,     N-methylpiperazine, morpholine or thiomorpholine; -   R⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R¹¹ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl,     aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl), or —NR⁶R⁷; -   R¹² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁-C₆     alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³²,     —COR³², —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,     thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,     benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or     indazolyl, each optionally substituted with 1 to 3 substituents     independently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³², —COR³²,     —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 3 substituents independently     selected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄     haloalkyl, cyano, —OR³⁰, SH, —S(O)_(n)R³², —COR³², —CO₂R³²,     —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰, —NR²⁹CO₂R³²,     —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   R²⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, phenyl, or     phenyl(C₁-C₄ alkyl)-; -   R²⁹ and R³⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R³² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; and -   n is 0, 1, or 2.

Preferred compounds of this invention are compounds of Formula (I-a) and pharmaceutically acceptable salts and pro-drug form thereof, wherein:

-   W is (—H, —H); -   Y is CH₂; -   R¹ is independently, at each occurrence, selected from H, halogen,     —CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, and C₄-C₈ cycloalkylalkyl;     -   wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, or C₄-C₈ cycloalkylalkyl is each optionally         substituted with halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰,         —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or —S(O)_(n)R¹²; -   R² is H, halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, NR⁹COR⁹, —COR¹⁰,     —OR¹⁰, SH, —S(O)_(n)R¹², C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇         cycloalkylalkyl is optionally substituted with halogen, —CN,         C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or         —S(O)_(n)R¹²; -   R³ is C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀     cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₈ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀         alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano,         —OR⁷, SH, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂, —NR⁷CONR⁶R⁷,         —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and         heterocyclyl; -   alternatively, R³ is —OR^(3a), —NR^(3a)R^(3b), —NHR^(3a),     —SO_(n)R^(3a), —SO₂NHR^(3a), —SO₂NR^(3a)R^(3b), —COR^(3a),     —CONHR^(3a), or CONR^(3a)R^(3b); -   R^(3a) and R^(3b) are independently selected from C₁-C₁₀ alkyl,     C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀ cycloalkenyl, and C₆-C₁₀     cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl may be replaced with O, S         or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, and C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1 to 3 substituents independently selected at         each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀ alkynyl,         C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano, —OR⁷, —SH,         —S(O)_(n)R¹¹, —COR⁶, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂,         —NR⁷CONR⁶R⁷, —NR⁷CO₂R⁸, —NR⁶R⁷, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and heterocyclyl; -   R⁴ is independently selected in each occurrence from —H, —OR¹⁰,     —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², halogen, C₁-C₆     alkyl, C₁-C₄ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₆     alkenyl, C₂-C₆ alkynyl, aryl and heteroaryl;     -   wherein C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ is CH; -   A² is CH; -   R⁵ is independently at each occurrence —H, C₁-C₁₀ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,     —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹, —CO₂R⁸, or     —S(O)_(n)R¹¹;     -   wherein C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, or —S(O)_(n)R¹¹; -   alternatively, two R⁵ groups on adjacent atoms can form a 5-7     membered fused ring, partially saturated or unsaturated, optionally     containing 1-2 —O— or —SO_(n)— or 1-3 N heteroatoms provided the     ring does not contain any S—S, O—O, S—O or N—S bonds;     -   said 5-7 membered fused ring optionally substituted with C₁-C₄         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₈         cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,         NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO₂R⁸, —CO(NOR⁹)R⁷, or         —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₄     haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   alternatively NR⁶R⁷ is piperidine, pyrrolidine, piperazine,     N-methylpiperazine, morpholine or thiomorpholine; -   R⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R¹¹ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl,     aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl), or —NR⁶R⁷; -   R¹² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁-C₆     alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³²,     —COR³², —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR² 9CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,     thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,     benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or     indazolyl, each optionally substituted with 1 to 3 substituents     independently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³², —COR³²,     —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 3 substituents independently     selected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄     haloalkyl, cyano, —OR³⁰, SH, —S(O)_(n)R³², —COR³², —CO₂R³²,     —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰, —NR²⁹CO₂R³²,     —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   R²⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, phenyl, or     phenyl(C₁-C₄ alkyl)-; -   R²⁹ and R³⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R³² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; and -   n is 0, 1, or 2.

More preferred compounds of this invention are compounds of Formula (I-a) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

-   W is (—H, —H); -   Y is CH₂; -   R¹ is a halogen; -   R³ is C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or     C₂-C₁₀ alkoxyalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; -   R⁴ and R⁵ are independently selected at each occurrence from —OR¹⁰,     halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkoxy; -   A¹ is CH; -   A² is CH; -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl.

Even more preferred compounds of this invention are compounds of Formula (I-a) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

-   W is (—H, —H); -   Y is CH₂; -   R¹ is a halogen; -   R³ is C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or     C₂-C₁₀ alkoxyalkyl; -   R⁴ and R⁵ are independently selected in each occurrence from —OR¹⁰,     halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkoxy; -   A¹ is CH; -   A² is CH; and -   R¹⁰ is independently at each occurrence selected from C₁-C₄ alkyl.

Specifically preferred compounds of this invention are compounds of Formula (I-a), pharmaceutically acceptable salts and pro-drug forms thereof, which are:

5-Chloro-1-(1-cyclopropylpropyl)-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone;

5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone;

5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

5-Chloro-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; and

5-Chloro-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone.

In another embodiment of preferred compounds of the present invention are compounds of Formula (I):

or a pharmaceutically acceptable salt form thereof, wherein:

-   W is (—H, —H); -   Y is —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, or —OCH₂—; -   R¹ is H, halogen, —CN, C₁-C₂ haloalkyl, —OR¹⁰, C₁-C₄ alkyl, C₂-C₄     alkenyl, C₂-C₄ alkynyl, C₃-C₄ cycloalkyl, and C₄-C₆ cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl, is         each optionally substituted with F, Cl, Br, CN, —OH, —CH₃,         —OCH₃, —CF₃, or —OCF₃; -   R^(2a) is H, F, Cl, Br, —CN, —OH, —CH₃, —OCH₃, —CF₃, or —OCF₃; -   R³ is C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈ alkynyl, C₃-C₆ cycloalkyl,     C₄-C₁₀ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₆ cycloalkenyl, or     C₆-C₁₀ cycloalkenylalkyl;     -   wherein each C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈ alkynyl, C₃-C₆         cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₆         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from methyl, ethyl, cyclopropyl, cyclobutyl,         F, Cl, Br, —CF₃, cyano, —OR⁷, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸,         —OC(O)NR⁶R⁷, —N₃, —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶,         —N(COR⁶)₂, —NR⁷CONR⁶R⁷, —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, and —CO₂H; -   alternatively, R³ is —S(O)R^(3a), —S(O)₂R^(3a), —COR^(3a),     —CONHR^(3a), or —CONR^(3a)R^(3b); -   R^(3a) and R^(3b) are independently selected from C₁-C₈ alkyl, C₃-C₈     alkenyl, C₃-C₈ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀ cycloalkylalkyl,     C₂-C₁₀ alkoxyalkyl, C₅-C₆ cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein each C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈ alkynyl, C₃-C₆         cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₆         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from methyl, ethyl, methoxy, ethoxy,         methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, F, Cl, —CF₃, and         —OCF₃: -   R⁴ is —H, —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰,     —S(O)_(n)R¹²—S(O)₂NR⁹R¹⁰, —NO₂, halogen, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or     C₂-C₄ alkynyl;     -   wherein C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄         alkenyl, or C₂-C₄ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ is CR⁵; -   A² is CR⁵; -   R⁵ is independently selected at each occurrence from —H, C₁-C₆     alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, —NO₂, halogen,     —CN, —NR⁶R⁷, —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹,     —CO₂R⁸, —S(O)₂NR⁹R¹⁰, and —S(O)_(n)R¹¹;     -   wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₀ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, and —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, methyl, ethyl,     propyl, or butyl; -   R⁸ is independently at each occurrence methyl, ethyl, propyl, or     butyl; -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     methyl, ethyl, propyl, or butyl; -   R¹¹ is independently at each occurrence H, methyl, ethyl, propyl,     butyl, or —NR⁶R⁷; -   R¹² is independently at each occurrence methyl, ethyl, propyl, or     butyl; and -   n is 0, 1, or 2.

Preferred compounds of this invention are compounds of Formula (I-b):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, halogen, —CN, C₁-C₂ haloalkyl, —OR¹⁰, or C₁-C₃ alkyl; -   R³ is C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkoxyalkyl, C₅-C₆ cycloalkenyl, or     C₆-C₇ cycloalkenylalkyl;     -   wherein each C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆         cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkoxyalkyl, C₅-C₆         cycloalkenyl, or C₆-C₇ cycloalkenylalkyl is optionally         substituted with 1 or 2 substituents independently selected at         each occurrence from methyl, ethyl, methoxy, ethoxy, methyl-S—,         ethyl-S—, cyclopropyl, cyclobutyl, F, Cl, —CF₃ and —OCF₃; -   R⁴ is —H, —OR¹⁰, —CN, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —NO₂, halogen, C₁-C₄     alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₂-C₄ alkenyl, C₂-C₄     alkynyl, —SR¹², —S(O)R¹², or —S(O)₂R¹²; -   R⁵ is independently at each occurrence —H, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₄     cycloalkyl, C₄-C₅ cycloalkylalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,     —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —S(O)₂NR⁹R¹⁰, —CO₂R⁸,     —SCH₃, —SCH₂CH₃, —S(O)R¹¹, or —S(O)₂R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, methyl, or ethyl; -   R⁸ is independently at each occurrence methyl or ethyl; -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     methyl, or ethyl; -   R¹¹ is independently at each occurrence methyl, ethyl, or —NR⁶R⁷;     and -   R¹² is independently at each occurrence methyl or ethyl.

More preferred compounds of this invention are compounds of Formula (I-c):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, —CN, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl; -   R³ is C₁-C₆ alkyl optionally substituted with 1 or 2 substituents     independently selected at each occurrence from methyl, ethyl,     methoxy, ethoxy, methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, and     —CF₃; -   R⁴ is —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy,     ethoxy, propoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; and -   R⁵ is independently at each occurrence —H, F, Cl, Br, —CN, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, or     C₁-C₂ haloalkoxy.

Even more preferred compounds of this invention are compounds of Formula (I-c):

or a pharmaceutically acceptable salt form thereof, wherein: or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, methyl, ethyl, —CN, or —CF₃; -   R³ is butyl-, pentyl-, hexyl-, heptyl-, methoxy-ethyl-,     methoxy-propyl-, methoxy-butyl-, methoxy-pentyl-, methoxy-hexyl-,     methylthio-ethyl-, methylthio-propyl-, methylthio-butyl-,     methylthio-pentyl-, methylthio-hexyl-, 1-cyclopropyl-propyl-,     1-cyclopropyl-butyl-, 1-cyclopropyl-pentyl-, 1-cyclobutyl-propyl-,     1-cyclobutyl-butyl-, 1-cyclobutyl-pentyl,     1-cyclopropyl-1-(CF₃)-methyl-, 1-cyclopropyl-2-(CF₃)-ethyl-,     1-cyclopropyl-3-(CF₃)-propyl-, 1-cyclobutyl-1-(CF₃)-methyl-,     1-cyclobutyl-2-(CF₃)-ethyl-, or 1-cyclobutyl-3-(CF₃)-propyl-; -   R⁴ is H, methyl-, ethyl-, methoxy-, ethoxy-, isopropoxy-,     n-propoxy-, F, Cl, Br, —CF₃, —OCF₃, —OCHF₂, —CN; and -   R⁵ is independently at each occurrence, —H, methyl, ethyl, methoxy,     ethoxy, F, Cl, Br, or —CF₃.

Specifically preferred compounds of this invention are compounds of Formula (I), and pharmaceutically acceptable salts thereof, which are:

-   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone; -   5-Chloro-1-(1-ethylpropyl)-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   3-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone; -   3-(5-Methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-methylpropyl)-2(1H)-pyrazinone; -   -3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-methylpropyl)-2(1H)-pyrazinone; -   5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-methylpropyl)-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-methylpropyl)-2(1H)-pyrazinone; -   5-Bromo-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   5-Bromo-1-(1-ethylpropyl)-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Bromo-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Bromo-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Bromo-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[2-methyl-1-(1-methylethyl)propyl]-2(1H)-pyrazinone; -   3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-cyclobutylpropyl)-6-methyl-2(1H)-pyrazinone; -   3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-methylpropyl-2(1H)-pyrazinone; -   3-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-5-ethyl-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   6-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-4-(1-ethylpropyl)-4,5-dihydro-5-oxo-2-pyrazinecarbonitrile; -   3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   1-[6-Chloro-4-[(1R)-1-(methoxymethyl)propyl]-3,4-dihydro-3-oxopyrazinyl]-5-methoxy-2,3-dihydro-1H-indole-7-carbonitrile; -   5-Bromo-3-(5-bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone;     and -   5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone.

More preferred compounds of this invention are compounds of Formula (I-d):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, —CN, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl; -   R³ is C₁-C₆ alkyl optionally substituted with 1 or 2 substituents     independently selected at each occurrence from methyl, ethyl,     methoxy, ethoxy, methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, and     —CF₃; -   R⁴ is —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy,     ethoxy, propoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; and -   R⁵ is independently at each occurrence —H, F, Cl, Br, —CN, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, or     C₁-C₂ haloalkoxy.

Even more preferred compounds of this invention are compounds of Formula (I-d):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, methyl, ethyl, —CN, or —CF₃; -   R³ is butyl-, pentyl-, hexyl-, heptyl-, methoxy-ethyl-,     methoxy-propyl-, methoxy-butyl-, methoxy-pentyl-, methoxy-hexyl-,     methylthio-ethyl-, methylthio-propyl-, methylthio-butyl-,     methylthio-pentyl-, methylthio-hexyl-, 1-cyclopropyl-propyl-,     1-cyclopropyl-butyl-, 1-cyclopropyl-pentyl-, 1-cyclobutyl-propyl-,     1-cyclobutyl-butyl-, 1-cyclobutyl-pentyl,     1-cyclopropyl-1-(CF₃)-methyl-, 1-cyclopropyl-2-(CF₃)-ethyl-,     1-cyclopropyl-3-(CF₃)-propyl-, 1-cyclobutyl-1-(CF₃)-methyl-,     1-cyclobutyl-2-(CF₃)-ethyl-, or 1-cyclobutyl-3-(CF₃)-propyl-; -   R⁴ is H, methyl-, ethyl-, methoxy-, ethoxy-, isopropoxy-,     n-propoxy-, F, Cl, Br, —CF₃, —OCF₃, —OCHF₂, —CN; and -   R⁵ is independently at each occurrence, —H, methyl, ethyl, methoxy,     ethoxy, F, Cl, Br, or —CF₃.

Specifically preferred compounds of this invention are compounds of Formula (I), and pharmaceutically acceptable salts thereof, which are:

-   3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; -   3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone; -   5-Bromo-3-(8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone;     and -   3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone.

More preferred compounds of this invention are compounds of Formula (I-e):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, —CN, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl; -   R³ is C₁-C₆ alkyl optionally substituted with 1 or 2 substituents     independently selected at each occurrence from methyl, ethyl,     methoxy, ethoxy, methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, and     —CF₃; -   R⁴ is —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy,     ethoxy, propoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; and -   R⁵ is independently at each occurrence —H, F, Cl, Br, —CN, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, or     C₁-C₂ haloalkoxy.

Even more preferred compounds of this invention are compounds of Formula (I-e):

or a pharmaceutically acceptable salt form thereof, wherein:

-   R¹ is H, F, Cl, Br, methyl, ethyl, —CN, or —CF₃; -   R³ is butyl-, pentyl-, hexyl-, heptyl-, methoxy-ethyl-,     methoxy-propyl-, methoxy-butyl-, methoxy-pentyl-, methoxy-hexyl-,     methylthio-ethyl-, methylthio-propyl-, methylthio-butyl-,     methylthio-pentyl-, methylthio-hexyl-, 1-cyclopropyl-propyl-,     1-cyclopropyl-butyl-, 1-cyclopropyl-pentyl-, 1-cyclobutyl-propyl-,     1-cyclobutyl-butyl-, 1-cyclobutyl-pentyl,     1-cyclopropyl-1-(CF₃)-methyl-, 1-cyclopropyl-2-(CF₃)-ethyl-,     1-cyclopropyl-3-(CF₃)-propyl-, 1-cyclobutyl-1-(CF₃)-methyl-,     1-cyclobutyl-2-(CF₃)-ethyl-, or 1-cyclobutyl-3-(CF₃)-propyl-; -   R⁴ is H, methyl-, ethyl-, methoxy-, ethoxy-, isopropoxy-,     n-propoxy-, F, Cl, Br, —CF₃, —OCF₃, —OCHF₂, —CN; and -   R⁵ is independently at each occurrence, —H, methyl, ethyl, methoxy,     ethoxy, F, Cl, Br, or —CF₃.

Specifically preferred compounds of this invention are compounds of Formula (I), and pharmaceutically acceptable salts thereof, which are:

-   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1R)-(1-methoxymethyl)propyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-(1-methoxymethyl)propyl]-2(1H)-pyrazinone; -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone; -   5-chloro-1-(1-cyclobutylpropyl)-3-(7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2(1H)-pyrazinone; -   5-chloro-1-[(1R)-1-cyclopropylpropyl]-3-(7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2(1H)-pyrazinone;     and -   3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone.

A second embodiment of preferred compounds of this invention are compounds of Formula (II):

or a pharmaceutically acceptable salt or pro-drug form thereof, wherein:

-   X is N; -   W is (—H, —H); -   Y is CH₂; -   B is NHR³; -   R¹ is independently, at each occurrence, selected from H, halogen,     —CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, and C₄-C₈ cycloalkylalkyl;     -   wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, or C₄-C₈ cycloalkylalkyl is each optionally         substituted with halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰,         —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or —S(O)_(n)R¹²; -   R² is H, halogen, CN, C₁-C₄ haloalkyl, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇         cycloalkylalkyl is optionally substituted with halogen, —CN,         C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or         —S(O)_(n)R¹²; -   R³ is C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀     cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₈ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀         alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano,         —OR⁷, SH, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂, —NR⁷CONR⁶R⁷,         —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and         heterocyclyl; -   R⁴ is independently selected in each occurrence from —H, —OR¹⁰,     —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², halogen, C₁-C₆     alkyl, C₁-C₄ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₆     alkenyl, C₂-C₆ alkynyl, aryl and heteroaryl;     -   wherein C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ are CH; -   A² are CH; -   R⁵ is independently at each occurrence —H, C₁-C₁₀ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,     —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹, —CO₂R⁸, or     —S(O)_(n)R¹¹;     -   wherein C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, or —S(O)_(n)R¹¹; -   alternatively, two R⁵ groups on adjacent atoms can form a 5-7     membered fused ring, partially saturated or unsaturated, optionally     containing 1-2 —O— or —SO_(n)— or 1-3 N heteroatoms provided the     ring does not contain any S—S, O—O, S—O or N—S bonds;     -   said 5-7 membered fused ring optionally substituted with C₁-C₄         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₈         cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,         NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO₂R⁸, —CO(NOR⁹)R⁷, or         —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₄     haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   alternatively NR⁶R⁷ is piperidine, pyrrolidine, piperazine,     N-methylpiperazine, morpholine or thiomorpholine; -   R⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R¹¹ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl,     aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl), or —NR⁶R⁷; -   R¹² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁-C₆     alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³²,     —COR³², —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,     thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,     benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or     indazolyl, each optionally substituted with 1 to 3 substituents     independently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³², —COR³²,     —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 3 substituents independently     selected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄     haloalkyl, cyano, —OR³⁰, SH, —S(O)_(n)R³², —COR³², —CO₂R³²,     —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰, —NR²⁹CO₂R³²,     —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   R²⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, phenyl, or     phenyl(C₁-C₄ alkyl)-; -   R²⁹ and R³⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R³² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; and -   n is 0, 1, or 2.

More preferred compounds of the second embodiment of this invention are compounds of Formula (II) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

-   X is N; -   W is (—H, —H); -   Y is CH₂; -   B is NHR³; -   R¹ is C₁-C₆ alkyl; -   R² is H, halogen, CN, or —COR¹⁰; -   R⁴ and R⁵ are independently selected in each occurrence —OR¹⁰,     halogen, or C₁-C₆ haloalkoxy; -   A¹ and A² are CH; and -   R¹⁰ is H.

Specifically preferred compounds of the second embodiment of this invention are compounds of Formula (II), pharmaceutically acceptable salts and pro-drug forms thereof, which are:

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine;

5-chloro-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine;

5-bromo-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine;

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-iodo-2-methylpyrimidine;

5-cyano-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine;

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine;

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-hydroxymethyl-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-(1-ethylpropylamino)-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-ethyl-3-methoxy)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-ethyl-3-methoxy)propylamino]-5-iodo-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-[1-(1-ethyl-3-methoxy)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-iodo-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-formyl-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-methylbutylamino)-2-methylpyrimidine;

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-methylpropylamino)-2-methylpyrimidine; and

4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-cyclobutyl)ethylamino)-2-methylpyrimidine.

A third embodiment of preferred compounds of this invention are compounds of Formula (II) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

-   X is CR¹; -   W is (—H, —H); -   Y is CH₂; -   B is NHR³; -   R¹ is independently, at each occurrence, selected from H, halogen,     —CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, and C₄-C₈ cycloalkylalkyl;     -   wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, or C₄-C₈ cycloalkylalkyl is each optionally         substituted with halogen, CN, C₁-C₄ haloalkyl, —NR⁹R¹⁰,         —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or —S(O)_(n)R¹²; -   R² is H, halogen, CN, C₁-C₄ haloalkyl, —COR¹⁰, —OR¹⁰, SH,     —S(O)_(n)R¹², C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl;     -   wherein each C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or C₄-C₇         cycloalkylalkyl is optionally substituted with halogen, —CN,         C₁-C₄ haloalkyl, —NR⁹R¹⁰, —NR⁹COR⁹, —COR¹⁰, —OR¹⁰, SH or         —S(O)_(n)R¹²; -   R³ is C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀     cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl;     -   wherein one carbon in any cycloalkyl ring may be replaced with         O, S or NR⁹; and     -   wherein each C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₈ alkynyl, C₃-C₈         cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₁₀ alkoxyalkyl, C₅-C₁₀         cycloalkenyl, or C₆-C₁₀ cycloalkenylalkyl is optionally         substituted with 1, 2 or 3 substituents independently selected         at each occurrence from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀         alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, cyano,         —OR⁷, SH, —S(O)_(n)R¹¹, —COR⁶, —NHR⁶SO₂R⁸, —OC(O)NR⁶R⁷, —N₃,         —OC(O)OR⁷, —CO₂R⁸, —OC(O)R⁶, —NR⁷COR⁶, —N(COR⁶)₂, —NR⁷CONR⁶R⁷,         —NR⁷CO₂R⁸, —NR⁶R⁷, —CONR⁶R⁷, —CO₂H, aryl, heteroaryl and         heterocyclyl; -   R⁴ is independently selected in each occurrence from —H, —OR¹⁰,     —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², halogen, C₁-C₆     alkyl, C₁-C₄ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₆     alkenyl, C₂-C₆ alkynyl, aryl and heteroaryl;     -   wherein C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl, are optionally substituted with         —OR¹⁰, —COR⁹, —CO₂R⁸, —CONR⁹R¹⁰, —CN, —NR⁹R¹⁰, —S(O)_(n)R¹², or         halogen; -   A¹ are CH; -   A² are CH; -   R⁵ is independently at each occurrence —H, C₁-C₁₀ alkyl, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆     cycloalkyl, C₄-C₁₂ cycloalkylalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,     —NR⁶COR⁷, —NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO(NOR⁹)R¹¹, —CO₂R⁸, or     —S(O)_(n)R¹¹;     -   wherein C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆         cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₄-C₈ cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂,         halogen, —CN, —NR⁶R⁷, —NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷,         —CO₂R⁸, —CO(NOR⁹)R⁷, or —S(O)_(n)R¹¹; -   alternatively, two R⁵ groups on adjacent atoms can form a 5-7     membered fused ring, partially saturated or unsaturated, optionally     containing 1-2 —O— or —SO_(n)— or 1-3 N heteroatoms provided the     ring does not contain any S—S, O—O, S—O or N—S bonds;     -   said 5-7 membered fused ring optionally substituted with C₁-C₄         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₈         cycloalkylalkyl, C₁-C₄ haloalkyl, —NO₂, halogen, —CN, —NR⁶R⁷,         NR⁶COR⁷, NR⁶CO₂R⁸, —COR⁶—OR⁷, —CONR⁶R⁷, —CO₂R⁸, —CO(NOR⁹)R⁷, or         —S(O)_(n)R¹¹; -   R⁶ and R⁷ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₄     haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂     cycloalkylalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   alternatively NR⁶R⁷ is piperidine, pyrrolidine, piperazine,     N-methylpiperazine, morpholine or thiomorpholine; -   R⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,     heteroaryl or heteroaryl(C₁-C₄ alkyl); -   R⁹ and R¹⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R¹¹ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl,     aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl), or —NR⁶R⁷; -   R¹² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁-C₆     alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³²,     —COR³², —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,     thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,     benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or     indazolyl, each optionally substituted with 1 to 3 substituents     independently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     halogen, C₁-C₄ haloalkyl, cyano, —OR³⁰, —SH, —S(O)_(n)R³², —COR³²,     —CO₂R²⁸, —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰,     —NR²⁹CO₂R²⁸, —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 3 substituents independently     selected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄     haloalkyl, cyano, —OR³⁰, SH, —S(O)_(n)R³², —COR³², —CO₂R³²,     —OC(O)R³², —NR²⁹COR²⁹, —N(COR³²)₂, —NR²⁹CONR²⁹R³⁰, —NR²⁹CO₂R³²,     —NR²⁹R³⁰, and —CONR²⁹R³⁰; -   R²⁸ is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, phenyl, or     phenyl(C₁-C₄ alkyl)-; -   R²⁹ and R³⁰ are independently at each occurrence selected from H,     C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆     cycloalkyl, C₂-C₆ alkoxyalkyl, and C₄-C₇ cycloalkylalkyl; -   R³² is independently at each occurrence C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇     cycloalkylalkyl; and -   n is 0, 1, or 2.

In a fourth embodiment the present invention provides for a pharmaceutical composition comprising a compound of Formula (I), (I-a), (I-b), or (I-c) and a pharmaceutically acceptable carrier.

Also provided herein is a pharmaceutical composition comprising a compound of Formula (II) and a pharmaceutically acceptable carrier.

In a fifth embodiment the present invention provides for a method of treating a mammal afflicted with affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis or hypoglycemia which method comprises administering to the mammal a therapeutically effective dose of a pharmaceutical composition provided herein.

In a preferred embodiment the present invention provides for a method of treating a mammal afflicted with anxiety or depression.

In a more preferred embodiment the present invention provides for a method of treating a mammal afflicted with anxiety.

In a more preferred embodiment the present invention provides for a method of treating a mammal afflicted with depression.

In a fifth embodiment, the present invention provides a compound of Formula (I), (I-a), (I-b), (I-c) or (II) for use in therapy.

In a preferred embodiment the present invention provides a compound of Formula (I), (I-a), (I-b), (I-c) or (II) for use in therapy of anxiety or depression.

In a sixth embodiment, the present invention provides for the use of a compound of Formula (I), (I-a), (I-b), (I-c) or (II) for the manufacture of a medicament for the treatment of anxiety or depression.

DEFINITIONS

Many compounds of this invention have one or more assymetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms or a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e. ═O), then 2 hydrogens on the atom are replaced. Unsubstituted atoms bear all of the hydrogen atoms dictated by their valency. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When any variable (e.g. R⁵) may optionally be substituted with more than one substituent (e.g. 1 to 3), the selection of substituent, at each occurrence, is independent of every other occurrence. Thus, for example, if variable R⁵ is optionally substituted with 1 to 3 defined substituents, then said variable R⁵ may be substituted with 0, 1, 2 or 3 defined substituents and those defined substituents are independently selected from the defined Markush group of available substituents. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Similarly, when a group of substituents (e.g. alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkylalkyl) may optionally be substituted with more than one substituent (e.g. 1 to 3), then each substituent of the group, as specified, may optionally be substituted as defined. Thus, for example, as used herein: C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and/or C₄-C₇ cycloalkylalkyl may optionally be substituted with 1 to 3 defined substituents, is intended to mean C₁-C₆ alkyl may optionally be substituted as defined, C₂-C₆ alkenyl may optionally be substituted as defined, C₂-C₆ alkynyl may optionally be substituted as defined, and so on. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C₁-C₆ alkyl” denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred “alkyl” group, unless otherwise specified, is “C₁-C₄ alkyl”. Additionally, unless otherwise specified, “propyl” denotes n-propyl or i-propyl; “butyl” denotes n-butyl, i-butyl, sec-butyl, or t-butyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of “C₂-C₆ alkenyl” include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.

As used herein, “alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. “Alkoxyalkyl” represents an alkoxy group, as defined herein, attached through an alkyl group, as defined above, with the indicated number of carbon atoms. For example, “C₂-C₆ alkoxyalkyl” includes (C₁-C₅ alkoxy)methyl, (C₁-C₄ alkoxy)ethyl, (C₁-C₃ alkoxy)propyl, (C₁-C₂ alkoxy)butyl, and (C₁ alkoxy)pentyl. For example, “C₂-C₆ alkoxyalkyl” includes methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro, chloro, and bromo.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like.

“Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C₃-C₆ cycloalkyl” denotes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. “Cycloalkylalkyl” represents a cycloalkyl group, as defined herein, attached through an alkyl group, as defined above, with the indicated number of carbon atoms. For example, “C₄-C₈ cycloalkylalkyl” includes, but is not limited to, (C₃-C₆ cycloalkyl)methyl, (C₃-C₆ cycloalkyl)ethyl, (C₃-C₅ cycloalkyl)propyl, and (C₃-C₄ cycloalkyl)butyl. For example, “C₄-C₈ cycloalkylalkyl” includes, but is not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, and the like.

“Cycloalkenyl” is intended to include partially unsaturated ring groups, having the specified number of carbon atoms. For example, “C₅-C₁₀ cycloalkenyl” includes, but is not limited to, cyclopentenyl, cyclohexenyl, cyclohexa-1,3-dienyl, cycloheptenyl, and the like. “Cycloalkenylalkyl” represents a cycloalkenyl group, as defined herein, attached through an alkyl group, as defined above, with the indicated number of carbon atoms.

As used herein, the term “aryl” or “C₆-C₁₀ aryl” is intended to mean either the 6-carbon benzene ring or the condensed 6-carbon rings of other aromatic derivatives containing the specified number of carbon atoms (see, e.g., Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New York (1997)). Aryl groups include, without limitation, phenyl, napthyl, indanyl and indenyl. Preferred “aryl” is phenyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF₃, SCH₃, S(O)CH₃, SO₂CH₃, —N(CH₃)₂, N(CH₃)H, CN, NO₂, OCF₃, C(═O)CH₃, CO₂H, or CO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclyl” is intended to mean a stable 5- to 7-membered monocyclic ring or 7- to 14-membered bicyclic ring system which is saturated or partially saturated (partially unsaturated), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S. Bicyclic heterocycles is intended to include saturated or partially saturated monocyclic heterocyclyl rings fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle is greater than 1, then these S and O heteroatoms are not adjacent to one another; i.e. there are no S—S, S—O, or O—O bonds in the heterocycle. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

As used herein, the term “heteroaryl” is intended to mean a stable 5- to 6-membered monocyclic ring or 9- to 10-membered bicyclic ring system which is fully unsaturated (aromatic), unless otherwise specified in the claims, and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heteroaryl may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heteroaryl may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heteroaryl is greater than 1, then these S and O heteroatoms are not adjacent to one another; i.e. there are no S—S, S—O, or O—O bonds in the heteroaryl. It is preferred that the total number of S and O atoms in the heteroaryl is not more than 1.

Examples of heterocycles (heterocyclyls) and heteroaryls include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred heteroaryls include, without limitation: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl.

As used herein, compounds of Formula (I-a), (I) or (II) contain a bicyclic group of formula:

wherein W, as defined in the claims may be ═O, ═S, —H or (H,H); and Y, as defined in the claims can be —C(═O)—, —CH₂—, —CH₂CH₂—, —OCH₂—, —SO_(n)CH₂—, —N═, —NR^(Y)—, —O—, or —CH═. It is understood by one skilled in the art that the dashed line in the bicyclic group can not form two double bonds. For example, when W is ═O or ═S (forming a C═O or C═S bond with the bicyclic ring) then Y is not —N═ or —CH═. When W is —H (forming a C—H bond with the bicyclic ring) then Y is —N═ or —CH═. Lastly, when W is (H,H), then W forms two C—H bonds with the bicyclic group, i.e. a —CH₂— moiety, and Y is not —N═ or —CH═. It is intended that combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Examples wherein W is (H,H), include, but are not limited to:

each substituted by R^(Y), R⁴ and R⁵, respectively.

Examples wherein W is (H,H), and A¹ and/or A² are N include, but are not limited to:

each substituted by R^(Y), R⁴ and R⁵, respectively.

Examples wherein W is C═O, include, but are not limited to:

each substituted by R^(Y), R⁴ and R⁵, respectively.

Examples wherein W is C═S, include, but are not limited to:

each substituted by R^(Y), R⁴ and R⁵, respectively.

Examples wherein W is —H, include, but are not limited to:

each substituted by R⁴ and R⁵, respectively.

“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

“Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of Formula (I-a) and (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula (I-a) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples or prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I-a) and (II), and the like.

The term “therapeutically effective amount” of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Compounds provided herein can be prepared, for example and without limitation, by the following synthetic schemes outlined below (Schemes 1-3):

A 4,6-dicloropyrimidine 1 was coupled with a heterocyclic amine 2 to give the corresponding adduct 3, under thermal conditions, by action of a base such as sodium hydride, sodium potassium, or lithium hexamethyldisilazide, sodium or potassium metal, lithium diisopropylamide or a related base in a solvent such as THF, dimethoxyethane, ether, DMF, or DMSO; or an acid such as HCl or p-toluensulfonic acid. A primary or secondary amine was added to 3 to give the aminopyrimidine 4. The 5-unsubstituted pyrimidine analogs (R²=H) could be halogenated on the 5-position to give compounds of compound 5 (R²=halogen) by the action of a halogenating agent such as Cl₂, Br₂, I₂, N-chloro, N-bromo or N-iodosuccinimide. The 5-iodopyrimidines of compound 5 (R²=I) were further transformed to the corresponding 5-cyano derivative of compound 6 (R²=CN) by the action of CuCN or CuCN/NaCN. The cyano group could be reduced to give 5-formyl or 5-aminomethyl derivatives of compound 7 (R²=CHO, R⁴=OMe).

The 5-pyrimidine position of compounds of compound 4 (R²=H, R⁴=Cl) could be formylated directly by the action of dichloromethylmethyl ether in the presence of a Lewis acid such as an AlCl₃, TiCl₄, SnCl₄, etc. to give compounds of compound 5 (R²=CHO, R³=Cl). The 5-formylpyrimidines of compounds 5 and 7 were further transformed to the corresponding 5-hydroxymethyl derivatives by the action of a reducing agent such as NaBH₄.

Compounds of Formula (II) may be synthesized as described in Scheme 2.

Coupling a suitably substituted aniline having an ortho —Br, —I, or —OSO₂CF₃ group with a pyrimidine of compound 1 under base, acid or thermal catalysis gave the coupled product of compound 9. The central nitrogen of 9 was reacted with a cinnamomyl halide in the presence of an amine base such as triethyl amine or pyridine in an aprotic solvent to give 10.

This compound in turn may be subjected to a palladium-catalyzed ring closure (see: Larock, R. C et. al. Tetrahedron Let., 1987, 44, 5291) to give compounds of compound 11, which when subjected to hydrolysis conditions afforded compounds of Formula (II) (W═O, Y═CH₂).

Alternatively the same analogs can be synthesized from intermediate of compound 12 as described by Tamura, Y. et. al. Synthesis, 1981, 534, to give 13, which upon desulfuration (see Tamura Y. et. al. Chem. Pharm. Bull. 1984, 32, 1995) can give compounds of Formula (II).

Analogs with the Formula (II) can be obtained by transformations described on Scheme 3.

Reaction of compounds of compound 16 with a suitably substituted acetylene using a suitable palladium catalyst such as, but not limited to Pd(PPh₃)₂Cl₂, Pd(PPh₃)₂Br₂, Pd(PPh₃)₄ etc. (see: Heck, R. F. et. al. Acc. Chem. Res., 1979, 12, 146) may provide the corresponding acetylenic aryls of compound 17. Depending on the original substitution on the acetylene, compounds of compound 17 can be converted to the 2-alkylindole analogs (Formula (II) in which W═H, Y═CH), or the indolinones (Formula II in which W═H, Y═CH).

The pyrazinones of this invention can be prepared by one of the general Schemes 4-10 outlined herein.

Compounds of the Formula (I-a) wherein R¹=halogen can be prepared as shown in Scheme 4. Reaction of a cyanide salt with formaldehyde and the appropriate substituted amine afforded the corresponding aminoacetonitrile which was purified as the hydrochloride salt of compound 20. Alternatively the same compounds of compound 20 can be synthesized by reaction of the amine H₂NR³ with a haloacetonitrile, such as chloroacetonitrile, in the presence of a base such as a tertiary amine or an inorganic base such as K₂CO₃ in an organic solvent and isolated as a salt of an inorganic acid by treatment with that acid. Amine salt of compound 20 was treated with an oxalyl halide, R¹COCOR¹, such as oxalyl chloride or bromide to afford the dihalo compound 21, as described in Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocyclic Chem. 20, 919, (1982). Compound 21 can be coupled with a secondary amine of compound 22 in the presence of a strong base such as NaH, KN(SiMe₃)₂, LiN(SiMe₃)₂ or NaN(SiMe₃)₂ in an aprotic organic solvent, or under acid catalysis to give compounds of Formula (I-a).

Compounds of the Formula (I-a) wherein R¹=alkyl or substituted alkyl can be prepared according to Scheme 5. Reaction of the intermediate of compound 21 in Scheme 4, wherein R¹=X″=halogen in Scheme 5, with an alkyl or aryl thiol, HSR″, in the presence of base such as NaH affords the adduct of compound 23, which may then be treated with a trialkylaluminum as described in Hirota, K.; Kitade, Y.; Kanbe, Y.; Maki, Y.; J. Org. Chem. 57, 5268, (1992), in the presence of a palladium catalyst, such as Pd(PPh₃)₂Cl₂, to give compounds of compound 24. Condensation of compounds of compound 24 with a secondary amine of compound 22 under thermal, base, or acid catalyzed conditions gives compounds of Formula (I-a). Alternatively intermediates of compound 24 may be oxidized to the corresponding sulfones with an oxidant such as KMnO₄ and then condensed with the secondary amines of compound 22 to give (I-a). The use of appropriately substituted aluminum alkyls, or simple transformations of those substituted alkyls can give access to compounds of Formula (I-a), where R¹ is a substituted alkyl; see Ratovelomanana, V.; Linstrumelle, G.; Tet. Letters 52, 6001 (1984) and references cited therein. Alternatively, compounds of Formula (I-a) wherein R¹=alkyl or substituted alkyl can be directly synthesized from compounds of Formula (I-a) wherein R¹=halogen as shown in Scheme 6 using the same synthetic methods described for the conversion of 23 to 24 shown in Scheme 5.

In Scheme 7, reaction of an aminoacetonitrile salt 20, described in Scheme 4, with an oxalyl halide ester 30 gives the corresponding amide 31, which in turn can be converted to the corresponding imidate salt 32. This can be cyclized under treatment with a base, such as K₂CO₃ or Et₃N to the pyrazinedione of compound 33. This can be converted to the corresponding halide 36, using a halogenating agent such as POX″₃, oxalyl halide or SOX″₂. Alternatively, 33 can be converted to the corresponding mesylate, tosylate or triflate, by treatment with the corresponding mesyl, tosyl, or triflic anhydride. Subsequently, 36 can be coupled with a secondary amine of compound 22 to give the corresponding adduct of compound 37, under the conditions described in Scheme 4.

Compounds of Formula (I-a) wherein R¹=COR¹⁰ or CO₂R¹⁰ can be synthesized from compounds of formula 23 by coupling with the appropriate vinyl aluminum or boron reagent in the presence of a palladium catalyst, such as Pd(PPh₃)₂Cl₂, and further transformations of the vinyl group, using methods known to one skilled in the art.

Compounds of Formula (I-a) wherein R¹=substituted N can be introduced on compounds of formula 32 by reaction with an amine to form the corresponding amidate 34 according to Scheme 8. Subsequently, 34 can be cyclized, halogenated, and substituted with the appropriate secondary amine 22 as described in Scheme 7 above.

Compounds of the Formula (I) wherein R¹=halogen can be prepared as shown in Scheme 9. Reaction of a cyanide salt with an aldehyde and the appropriate substituted amine affords the corresponding aminoacetonitrile which may be purified as the hydrochloride salt of compound 41. Alternatively the same compound 41 can be synthesized by reaction of the amine H₂NR³ with an appropriately substituted haloacetonitrile, such as 2-bromopropionitrile, in the presence of a base such as a tertiary amine or an inorganic base such as K₂CO₃ in an organic solvent and may be isolated as a salt of an inorganic acid by treatment with that acid. Amine salt of compound 41 was treated with an oxalyl halide, R¹COCOR¹, such as oxalyl chloride or bromide to afford the dihalo compound 42, as described in Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocyclic Chem. 20, 919, (1982). Compounds of compound 42 can be coupled with a secondary amine of compound 22 thermally, in the presence of a strong base such as NaH, KN(SiMe₃)₂, LiN(SiMe₃)₂ or NaN(SiMe₃)₂ in an aprotic organic solvent, or under acid catalysis to give compounds of Formula (I).

The compounds of Formula (I-a) and (I) where R¹, R² or R³ is a functional group not compatible with the procedures of Schemes 4-9 may be prepared from precursors where the interfering functionality of R¹, R² or R³ is protected using methods known to one skilled in the art (see T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, N.Y., 1991); or from precursors bearing R¹, R² or R³ groups amenable to later conversion into the desired functionality using standard methods (see J. March, Advanced Organic Chemistry, Wiley, N.Y., 1992).

Alternatively, compounds of Formula (I) wherein R¹=halogen can be prepared as shown in Scheme 10. Reaction of an aminoacetonitrile salt 20, described in Scheme 4, with an oxalyl halide ester 30, gives the corresponding amide 31, which can be converted to the corresponding imidate salt 32 in the presence of an acid such as HCl and an alcohol where R′ is a protecting group which can be removed later in the synthesis using conditions which will not destroy the structural integrity of the molecule. Examples of protecting groups which might be used include, but are not limited to, methyl, allyl, benzyl, p-methoxybenzyl and methoxymethyl. The imidate salt 32 can be cyclized under treatment with a base, such as K₂CO₃ or Et₃N to the pyrazinedione of Formula 33. R′ can then be removed using conditions appropriate for the choice of the protecting group known to one skilled in the art (see T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, N.Y., 1991). Intermediate 43 can be brominated using conditions such as Br₂/HOAc or NBS to give compounds of Formula 44. The bromide in compounds of Formula 44 may or may not be displaced. If it is desired to refunctionalize this group, it can be treated with other halides using reagents such as NaF, KF, LiF, NaCl, KCl, LiCl, NaI, KI or LiI. Alternatively, the bromide can be displaced with other nucleophiles such as —OR^(a) where R^(a)=C₁-C₃ alkyl, —NR^(a)R^(b) where R^(a) and R^(b) are independently H or C₁-C₃ alkyl or —SR^(a) where R^(a)=C₁-C₃ alkyl. If the bromide is displaced with —SR^(a), the resulting sulfide may be oxidized to either the sulfoxide or sulfone. In addition the bromide may be displaced with H₂S. The resulting thiol may be subsequently oxidized to form a sulfonic acid which may also be converted to the sulfonamide using conditions known to one skilled in the art of synthetic organic chemistry. The bromide may also be converted to a nitrile by treatment with various reagents such as, but not limited to KCN, NaCN and ZnCN/PdL₄. The resulting product 45 may be treated with a halogenating reagent, such as but not limited to POCl₃, POBr₃, (COCl)₂, (COBr)₂, SOCl₂ or SOBr₂ to form compounds of Formula 42 as described in Scheme 7. Subsequently, 42 may be coupled with a secondary amine of Formula 22 to give the corresponding adduct of Formula I under conditions described in Scheme 4. R¹ of Formula I may subsequently be converted to an alkyl group using conditions described in Schemes 5 or 6 provided that R^(2a) is a group other than bromide or iodide.

Intermediates wherein compound 22 is indoline or substituted indoline are well known in the art and/or synthesized by methods well known to one skilled in the art. For example, U.S. Pat. No. 6,245,769, issued Jun. 12, 2001, herein incorporated by reference, discloses examples of substituted indolines and the syntheses thereof.

Intermediates of compound 22 where Y═—OCH₂— can be prepared as illustrated in Scheme 11. An appropriate starting material such as 4-fluoro-2-nitrophenol can be treated with nucleophiles such as, but not limited to an alkali metal alkoxide such as sodium, potassium or lithium methoxide, sodium or potassium cyanide, alkylsufides, halide salts or alkali metal hydroxides in an organic solvent to give product 47. Reduction of the nitro group of 47 can be achieved with reagents such as, but not limited to H₂/Pd/C, SnCl₂.2H₂O or iron catalysts (preferably H₂/Pd/C) in an organic solvent appropriate for the chosen reaction conditions to give aminophenol 48. The resultant product 48 can be treated with a base such as, but not limited to alkali metal carbonates, alkali metal alkoxides or alkali metal hexamethyldisilazide bases (preferably K₂CO₃) and dibromoethane in an organic solvent such as acetone, acetonitrile, tetrahydrofuran, dioxane or DMF to form compounds of formula 49. These products can be treated with halogenating reagents such as, but not limited to pyridinium tribromide, N-bromosuccinimide, bromine, N-chlorosuccinimide, iodine, or iodine monobromide to give the corresponding halogenated products of formula 22. If desired, the halogen group at R⁵ may be refunctionalized by treatment with reagents such as but not limited to ZnCN/PdL₄ to form an aryl cyanide or ROH and Pd(OAc)₂/L or Ni(COD)₂/L to form an aryl ether. R⁵ may also be converted to an alkyl group by protection of the aniline nitrogen with a Boc group, treatment of the Boc protected product with n-BuLi or similar bases followed by addition of an alkylating agent such as methyl iodide and removal of the Boc group to form compounds of formula 22.

Various analogs synthesized using Schemes 1-11 are listed in the Tables below; as well as compounds envisioned by the invention.

TABLE 1

Ex. # X R³ R² R⁴ R⁵ Mp ° C. 1 N CHEt₂ H Cl Cl 116-117 2 N CHEt₂ Cl Cl Cl 132-134 3 N CHEt₂ Br Cl Cl 136-138 4 N CHEt₂ I Cl Cl 5 N CHEt₂ CN Cl Cl 163-165 6 N CHEt₂ CHO Cl Cl 182-184 7 N CHEt₂ CH₂OH Cl Cl 150-152 8 N CHEt₂ CH₂OMe Cl Cl 9 N CHEt₂ COMe Cl Cl 10 N CHEt₂ CHNOMe Cl Cl 11 N CHEt₂ OMe Cl Cl 12 N CHEt₂ SMe Cl Cl 13 N CHEt₂ SOMe Cl Cl 14 N CHEt₂ SO₂Me Cl Cl 15 N CHEt₂ CO₂Me Cl Cl 16 N CHEt₂ CONHMe Cl Cl 17 N CHEt₂ CONMe₂ Cl Cl 17a N CHEt₂ NO₂ Cl Cl 17b N CHEt₂

Cl Cl 17c N CHEt₂

Cl Cl 17d N CHEt₂

Cl Cl 18 N CHEt(CH₂OMe) H Cl Cl 19 N CHEt(CH₂OMe) Cl Cl Cl 20 N CHEt(CH₂OMe) Br Cl Cl 21 N CHEt(CH₂OMe) I Cl Cl 22 N CHEt(CH₂OMe) CN Cl Cl 23 N CHEt(CH₂OMe) CHO Cl Cl 24 N CHEt(CH₂OMe) CH₂OH Cl Cl 25 N CHEt(CH₂OMe) CH₂OMe Cl Cl 26 N CHEt(CH₂OMe) OMe Cl Cl 27 N CHEt(CH₂OMe) COMe Cl Cl 28 N CHEt(CH₂OMe) CHNOMe Cl Cl 29 N CHEt(CH₂OMe) SMe Cl Cl 30 N CHEt(CH₂OMe) SOMe Cl Cl 31 N CHEt(CH₂OMe) SO₂Me Cl Cl 32 N CHEt(CH₂OMe) CO₂Me Cl Cl 33 N CHEt(CH₂OMe) CONHMe Cl Cl 34 N CHEt(CH₂OMe) CONMe₂ Cl Cl 35 N CHEt(C₂H₄OMe) H Cl Cl 36 N CHEt(C₂H₄Ome) COMe Cl Cl 37 N CHEt(C₂H₄Ome) CHNOMe Cl Cl 38 N CHEt(C₂H₄Ome) Cl Cl Cl 30 N CHEt(C₂H₄Ome) Br Cl Cl 40 N CHEt(C₂H₄Ome) I Cl Cl 41 N CHEt(C₂H₄Ome) CN Cl Cl 42 N CHEt(C₂H₄Ome) CHO Cl Cl 43 N CHEt(C₂H₄Ome) CH₂OH Cl Cl 44 N CHEt(C₂H₄OMe) CH₂OMe Cl Cl 45 N CHEt(C₂H₄OMe) C(Me)NOMe Cl Cl 46 N CHEt(C₂H₄OMe) OMe Cl Cl 47 N CHEt(C₂H₄OMe) SMe Cl Cl 48 N CHEt(C₂H₄OMe) SOMe Cl Cl 49 N CHEt(C₂H₄OMe) SO₂Me Cl Cl 50 N CHEt(C₂H₄OMe) CO₂Me Cl Cl 51 N CHEt(C₂H₄OMe) CONHMe Cl Cl 52 N CHEt(C₂H₄OMe) CONMe₂ Cl Cl 53 N CHEt₂ H OMe Cl 54 N CHEt₂ COMe OMe Cl 55 N CHEt₂ CHNOMe OMe Cl 56 N CHEt₂ Cl OMe Cl 57 N CHEt₂ Br OMe Cl 58 N CHEt₂ I OMe Cl 59 N CHEt₂ CN OMe Cl 189-190 60 N CHEt₂ CHO OMe Cl 178-179 61 N CHEt₂ CH₂OH ONe Cl 62 N CHEt₂ CH₂OMe OMe Cl 63 N CHEt₂ OMe OMe Cl 64 N CHEt₂ SMe OMe Cl 65 N CHEt₂ SOMe OMe Cl 66 N CHEt₂ SO₂Me OMe Cl 67 N CHEt₂ CO₂Me OMe Cl 68 N CHEt₂ CONHMe OMe Cl 69 N CHEt₂ CONMe₂ OMe Cl 70 N CHEt(CH₂OMe) H OMe Cl 71 N CHEt(CH₂OMe) COMe OMe Cl 72 N CHEt(CH₂OMe) Cl OMe Cl 73 N CHEt(CH₂OMe) Br OMe Cl 74 N CHEt(CH₂OMe) I OMe Cl 150-152 75 N CHEt(CH₂OMe) CN OMe Cl 182-183 76 N CHEt(CH₂OMe) CHO OMe Cl 150-153 77 N CHEt(CH₂OMe) CH₂OH OMe Cl 148-150 78 N CHEt(CH₂OMe) CH₂OMe OMe Cl 79 N CHEt(CH₂OMe) OMe OMe Cl 80 N CHEt(CH₂OMe) SMe OMe Cl 81 N CHEt(CH₂OMe) SOMe OMe Cl 82 N CHEt(CH₂OMe) SO₂Me OMe Cl 83 N CHEt(CH₂OMe) CO₂Me OMe Cl 84 N CHEt(CH₂OMe) CONHMe OMe Cl 85 N CHEt(CH₂OMe) CONMe₂ OMe Cl 86 N CHEt(C₂H₄OMe) H OMe Cl 87 N CHEt(C₂H₄OMe) COMe OMe Cl 88 N CHEt(C₂H₄OMe) CHNOMe OMe Cl 89 N CHEt(C₂H₄OMe) Cl OMe Cl 90 N CHEt(C₂H₄OMe) Br OMe Cl 91 N CHEt(C₂H₄OMe) I OMe Cl 127-129 92 N CHEt(C₂H₄OMe) CN OMe Cl 137-139 93 N CHEt(C₂H₄OMe) CHO OMe Cl 125-128 94 N CHEt(C₂H₄OMe) CH₂OH OMe Cl 110-113 95 N CHEt(C₂H₄OMe) CH₂OMe OMe Cl 96 N CHEt(C₂H₄OMe) OMe OMe Cl 97 N CHEt(C₂H₄OMe) SMe OMe Cl 98 N CHEt(C₂H₄OMe) SOMe OMe Cl 99 N CHEt(C₂H₄OMe) SO₂Me OMe Cl 100 N CHEt(C₂H₄OMe) CO₂Me OMe Cl 101 N CHEt(C₂H₄OMe) CONHMe OMe Cl 102 N CHEt(C₂H₄OMe) CONMe₂ OMe Cl 103 N CHEt₂ H Me Cl 104 N CHEt₂ COMe Me Cl 105 N CHEt₂ CHNOMe Me Cl 106 N CHEt₂ Cl Me Cl 107 N CHEt₂ Br Me Cl 108 N CHEt₂ I Me Cl 115-116 109 N CHEt₂ CN Me Cl 155-157 110 N CHEt₂ CHO Me Cl 155-156 111 N CHEt₂ CH₂OH Me Cl 112 N CHEt₂ CH₂OMe Me Cl 113 N CHEt₂ OMe Me Cl 114 N CHEt₂ SMe Me Cl 115 N CHEt₂ SOMe Me Cl 116 N CHEt₂ SO₂Me Me Cl 117 N CHEt₂ CO₂Me Me Cl 118 N CHEt₂ CONHMe Me Cl 119 N CHEt₂ CONMe₂ Me Cl 120 N CHEt(CH₂OMe) H Me Cl 121 N CHEt(CH₂OMe) COMe Me Cl 122 N CHEt(CH₂OMe) CHNOMe Me Cl 123 N CHEt(CH₂OMe) Cl Me Cl 124 N CHEt(CH₂OMe) Br Me Cl 125 N CHEt(CH₂OMe) I Me Cl 135-138 126 N CHEt(CH₂OMe) CN Me Cl 135-138 127 N CHEt(CH₂OMe) CHO Me Cl 134-136 128 N CHEt(CH₂OMe) CH₂OH Me Cl 129 N CHEt(CH₂OMe) CH₂OMe Me Cl 130 N CHEt(CH₂OMe) OMe Me Cl 131 N CHEt(CH₂OMe) SMe Me Cl 132 N CHEt(CH₂OMe) SOMe Me Cl 133 N CHEt(CH₂OMe) SO₂Me Me Cl 134 N CHEt(CH₂OMe) CO₂Me Me Cl 135 N CHEt(CH₂OMe) CONHMe Me Cl 136 N CHEt(CH₂OMe) CONMe₂ Me Cl 137 N CHEt(C₂H₄OMe) H Me Cl 138 N CHEt(C₂H₄OMe) COMe Me Cl 139 N CHEt(C₂H₄OMe) CHNOMe Me Cl 140 N CHEt(C₂H₄OMe) Cl Me Cl 141 N CHEt(C₂H₄OMe) Br Me Cl 142 N CHEt(C₂H₄OMe) I Me Cl 99-100 143 N CHEt(C₂H₄OMe) CN Me Cl Amorphous 144 N CHEt(C₂H₄OMe) CHO Me Cl Amorphous 145 N CHEt(C₂H₄OMe) CH₂OH Me Cl 146 N CHEt(C₂H₄OMe) C(Me)NOMe Me Cl 147 N CHEt(C₂H₄OMe) CH₂OMe Me Cl 148 N CHEt(C₂H₄OMe) OMe Me Cl 149 N CHEt(C₂H₄OMe) SMe Me Cl 150 N CHEt(C₂H₄OMe) SOMe Me Cl 151 N CHEt(C₂H₄OMe) SO₂Me Me Cl 152 N CHEt(C₂H₄OMe) CO₂Me Me Cl 153 N CHEt(C₂H₄OMe) CONHMe Me Cl 154 N CHEt(C₂H₄OMe) CONMe₂ Me Cl 155 CH CHEt₂ H Cl Cl 156 CH CHEt₂ COMe Cl Cl 157 CH CHEt₂ CHNOMe Cl Cl 158 CH CHEt₂ Cl Cl Cl 159 CH CHEt₂ Br Cl Cl 160 CH CHEt₂ I Cl Cl 161 CH CHEt₂ CN Cl Cl 162 CH CHEt₂ CHO Cl Cl 163 CH CHEt₂ CH₂OH Cl Cl 164 CH CHEt₂ CH₂OMe Cl Cl 165 CH CHEt₂ OMe Cl Cl 166 CH CHEt₂ SMe Cl Cl 167 CH CHEt₂ SOMe Cl Cl 168 CH CHEt₂ SO₂Me Cl Cl 169 CH CHEt₂ CO₂Me Cl Cl 170 CH CHEt₂ CONHMe Cl Cl 171 CH CHEt₂ CONMe₂ Cl Cl 172 CH CHEt(CH₂OMe) H Cl Cl 173 CH CHEt(CH₂OMe) COMe Cl Cl 174 CH CHEt(CH₂OMe) CHNOMe Cl Cl 175 CH CHEt(CH₂OMe) Cl Cl Cl 176 CH CHEt(CH₂OMe) Br Cl Cl 177 CH CHEt(CH₂OMe) I Cl Cl 178 CH CHEt(CH₂OMe) CN Cl Cl 179 CH CHEt(CH₂OMe) CHO Cl Cl 180 CH CHEt(CH₂OMe) CH₂OH Cl Cl 181 CH CHEt(CH₂OMe) CH₂OMe Cl Cl 182 CH CHEt(CH₂OMe) OMe Cl Cl 183 CH CHEt(CH₂OMe) SMe Cl Cl 184 CH CHEt(CH₂OMe) SOMe Cl Cl 185 CH CHEt(CH₂OMe) SO₂Me Cl Cl 186 CH CHEt(CH₂OMe) CO₂Me Cl Cl 187 CH CHEt(CH₂OMe) CONHMe Cl Cl 188 CH CHEt(CH₂OMe) CONMe₂ Cl Cl 189 CH CHEt(C₂H₄OMe) H Cl Cl 190 CH CHEt(C₂H₄OMe) COMe Cl Cl 191 CH CHEt(C₂H₄OMe) CHNOMe Cl Cl 192 CH CHEt(C₂H₄OMe) Cl Cl Cl 193 CH CHEt(C₂H₄OMe) Br Cl Cl 194 CH CHEt(C₂H₄OMe) I Cl Cl 195 CH CHEt(C₂H₄OMe) CN Cl Cl 196 CH CHEt(C₂H₄OMe) CHO Cl Cl 197 CH CHEt(C₂H₄OMe) CH₂OH Cl Cl 198 CH CHEt(C₂H₄OMe) C(Me)NOMe Cl Cl 199 CH CHEt(C₂H₄OMe) CH₂OMe Cl Cl 200 CH CHEt(C₂H₄OMe) OMe Cl Cl 201 CH CHEt(C₂H₄OMe) SMe Cl Cl 202 CH CHEt(C₂H₄OMe) SOMe Cl Cl 203 CH CHEt(C₂H₄OMe) SO₂Me Cl Cl 204 CH CHEt(C₂H₄OMe) CO₂Me Cl Cl 205 CH CHEt(C₂H₄OMe) CONHMe Cl Cl 206 CH CHEt(C₂H₄OMe) CONMe₂ Cl Cl 207 CH CHEt(CH₂OMe) COMe OMe Cl 208 CH CHEt(CH₂OMe) CHNOMe OMe Cl 209 CH CHEt(CH₂OMe) Cl ONe Cl 210 CH CHEt(CH₂OMe) Br OMe Cl 211 CH CHEt(CH₂OMe) I OMe Cl 212 CH CHEt(CH₂OMe) CN OMe Cl 213 CH CHEt(CH₂OMe) CHO OMe Cl 214 CH CHEt(CH₂OMe) CH₂OH OMe Cl 215 CH CHEt(CH₂OMe) CH₂OMe OMe Cl 216 CH CHEt(CH₂OMe) OMe OMe Cl 217 CH CHEt(CH₂OMe) SMe OMe Cl 218 CH CHEt(CH₂OMe) SOMe OMe Cl 219 CH CHEt(CH₂OMe) SO₂Me OMe Cl 220 CH CHEt(CH₂OMe) CO₂Me OMe Cl 221 CH CHEt(CH₂OMe) CONHMe OMe Cl 222 CH CHEt(CH₂OMe) CONMe₂ OMe Cl 223 CH CHEt(C₂H₄OMe) H OMe Cl 224 CH CHEt(C₂H₄OMe) COMe OMe Cl 225 CH CHEt(C₂H₄OMe) CHNOMe OMe Cl 226 CH CHEt(C₂H₄OMe) Cl OMe Cl 227 CH CHEt(C₂H₄OMe) Br OMe Cl 228 CH CHEt(C₂H₄OMe) I OMe Cl 229 CH CHEt(C₂H₄OMe) CN OMe Cl 230 CH CHEt(C₂H₄OMe) CHO OMe Cl 231 CH CHEt(C₂H₄OMe) CH₂OH OMe Cl 232 CH CHEt(C₂H₄OMe) CH₂OMe OMe Cl 233 CH CHEt(C₂H₄OMe) OMe OMe Cl 234 CH CHEt(C₂H₄OMe) SMe OMe Cl 235 CH CHEt(C₂H₄OMe) SOMe OMe Cl 236 CH CHEt(C₂H₄OMe) SO₂Me OMe Cl 237 CH CHEt(C₂H₄OMe) CO₂Me OMe Cl 238 CH CHEt(C₂H₄OMe) CONHMe OMe Cl 239 CH CHEt(C₂H₄OMe) CONMe₂ OMe Cl 240 CH CHEt₂ H OMe Cl 241 CH CHEt₂ COMe OMe Cl 242 CH CHEt₂ CHNOMe OMe Cl 243 CH CHEt₂ Cl OMe Cl 244 CH CHEt₂ Br OMe Cl 245 CH CHEt₂ I OMe Cl 246 CH CHEt₂ CN OMe Cl 247 CH CHEt₂ CHO OMe Cl 248 CH CHEt₂ CH₂OH OMe Cl 249 CH CHEt₂ CH₂OMe OMe Cl 250 CH CHEt₂ OMe OMe Cl 251 CH CHEt₂ SMe OMe Cl 252 CH CHEt₂ SOMe OMe Cl 253 CH CHEt₂ SO₂Me OMe Cl 254 CH CHEt₂ CO₂Me OMe Cl 255 CH CHEt₂ CONHMe OMe Cl 256 CH CHEt₂ CONMe₂ OMe Cl 256a CH CHEt₂ NO₂ OMe Cl 256b CH CHEt₂ NCO₂CH₂CH(CH₃)₂ OMe Cl 256c CH CHEt₂ NO₂CH₃ OMe Cl 257 CH CHEt₂ H Me Cl 258 CH CHEt₂ COMe Me Cl 259 CH CHEt₂ CHNOMe Me Cl 260 CH CHEt₂ Cl Me Cl 261 CH CHEt₂ Br Me Cl 262 CH CHEt₂ I Me Cl 263 CH CHEt₂ CN Me Cl 264 CH CHEt₂ CHO Me Cl 265 CH CHEt₂ CH₂OH Me Cl 266 CH CHEt₂ CH₂OMe Me Cl 267 CH CHEt₂ OMe Me Cl 268 CH CHEt₂ SMe Me Cl 269 CH CHEt₂ SOMe Me Cl 270 CH CHEt₂ SO₂Me Me Cl 271 CH CHEt₂ CO₂Me Me Cl 272 CH CHEt₂ CONHMe Me Cl 273 CH CHEt₂ CONMe₂ Me Cl 274 CH CHEt(CH₂OMe) H Me Cl 275 CH CHEt(CH₂OMe) COMe Me Cl 276 CH CHEt(CH₂OMe) CHNOMe Me Cl 277 CH CHEt(CH₂OMe) Cl Me Cl 278 CH CHEt(CH₂OMe) Br Me Cl 279 CH CHEt(CH₂OMe) I Me Cl 280 CH CHEt(CH₂OMe) CN Me Cl 281 CH CHEt(CH₂OMe) CHO Me Cl 282 CH CHEt(CH₂OMe) CH₂OH Me Cl 283 CH CHEt(CH₂OMe) CH₂OMe Me Cl 284 CH CHEt(CH₂OMe) OMe Me Cl 285 CH CHEt(CH₂OMe) SMe Me Cl 286 CH CHEt(CH₂OMe) SOMe Me Cl 287 CH CHEt(CH₂OMe) SO₂Me Me Cl 288 CH CHEt(CH₂OMe) CO₂Me Me Cl 289 CH CHEt(CH₂OMe) CONHMe Me Cl 290 CH CHEt(CH₂OMe) CONMe₂ Me Cl 291 CH CHEt(C₂H₄OMe) H Me Cl 292 CH CHEt(C₂H₄OMe) COMe Me Cl 293 CH CHEt(C₂H₄OMe) CHNOMe Me Cl 294 CH CHEt(C₂H₄OMe) Cl Me Cl 295 CH CHEt(C₂H₄OMe) Br Me Cl 296 CH CHEt(C₂H₄OMe) I Me Cl 297 CH CHEt(C₂H₄OMe) CN Me Cl 298 CH CHEt(C₂H₄OMe) CHO Me Cl 299 CH CHEt(C₂H₄OMe) CH₂OH Me Cl 300 CH CHEt(C₂H₄OMe) C(Me)NOMe Me Cl 301 CH CHEt(C₂H₄OMe) CH₂OMe Me Cl 302 CH CHEt(C₂H₄OMe) OMe Me Cl 303 CH CHEt(C₂H₄OMe) SMe Me Cl 304 CH CHEt(C₂H₄OMe) SOMe Me Cl 305 CH CHEt(C₂H₄OMe) SO₂Me Me Cl 306 CH CHEt(C₂H₄OMe) CO₂Me Me Cl 307 CH CHEt(C₂H₄OMe) CONHMe Me Cl 308 CH CHEt(C₂H₄OMe) CONMe₂ Me Cl 309 N CH(nPr)Me H OMe Cl 310 N CH(Et)Me H OMe Cl 311 N CH(cBu)Me H OMe Cl

TABLE 2

Mass Spec (M + H) Ex. # R¹ R³ R⁴ R⁵ Melting Point ° C. 401 Cl CHEt₂ Cl Cl 386 168-170° C. 402 Cl CH(cPr)Et Cl Cl 398 403 Cl CH(cPr)Me Cl Cl 404 Cl CH(Et)CH₂OMe Cl Cl 402 405 Cl CH(cPr)CH₂OMe Cl Cl 406 Cl CH(cBu)CH₂OMe Cl Cl 407 Cl CH(nPr)CH₂OMe Cl Cl 408 Cl CH(CPr)C₂H₄OMe Cl Cl 409 Cl CH(cBu)C₂H₄OMe Cl Cl 410 Cl CH(Et)C₂H₄OMe Cl Cl 416 95-97° C. 411 Cl CHEt₂ OMe Cl 412 Cl CH(cPr)Et OMe Cl 413 Cl CH(Et)CH₂OMe OMe Cl 398 414 Cl CH(cPr)Me OMe Cl 415 Cl CH(cPr)CH₂OMe OMe Cl 416 Cl CH(cBu)CH₂OMe OMe Cl 417 Cl CH(nPr)CH₂OMe OMe Cl 418 Cl CH(cPr)C₂H₄OMe OMe Cl 419 Cl CH(cBu)C₂H₄OMe OMe Cl 420 Cl CH(Et)C₂H₄OMe OMe Cl 412 421 Cl CHEt₂ Me Cl 422 Cl CH(cPr)Et Me Cl 423 Cl CH(Et)CH₂OMe Me Cl 424 Cl CH(cPr)Me Me Cl 425 Cl CH(cPr)CH₂OMe Me Cl 426 Cl CH(cBu)CH₂OMe Me Cl 427 Cl CH(nPr)CH₂OMe Me Cl 428 Cl CH(cPr)C₂H₄OMe Me Cl 429 Cl CH(cBu)C₂H₄OMe Me Cl 430 Cl CH(Et)C₂H₄OMe Me Cl 431 Cl CHEt₂ OMe Me 362 164-165° C. 432 Cl CH(cPr)Et OMe Me 433 Cl CH(Et)CH₂OMe OMe Me 378 434 Cl CH(cPr)Me OMe Me 435 Cl CH(cPr)CH₂OMe OMe Me 436 Cl CH(CBu)CH₂OMe OMe Me 437 Cl CH(nPr)CH₂OMe OMe Me 438 Cl CH(cPr)C₂H₄OMe OMe Me 439 Cl CH(cBu)C₂H₄OMe OMe Me 440 Cl CH(Et)C₂H₄OMe OMe Me 392 441 Cl CHEt₂ OMe Br 426 130-132° C. 442 Cl CH(cPr)Et OMe Br 443 Cl CH(Et)CH₂OMe OMe Br 442 444 Cl CH(cPr)Me OMe Br 445 Cl CH(cPr)CH₂OMe OMe Br 446 Cl CH(cBu)CH₂OMe OMe Br 447 Cl CH(nPr)CH₂OMe OMe Br 448 Cl CH(cPr)C₂H₄OMe OMe Br 449 Cl CH(cBu)C₂H₄OMe OMe Br 450 Cl CH(Et)C₂H₄OMe OMe Br 454 451 Me CHEt₂ Cl Cl 366 137-139° C. 452 Me CH(cPr)Et Cl Cl 453 Me CH(Et)CH₂OMe Cl Cl 454 Me CH(cPr)Me Cl Cl 455 Me CH(cPr)CH₂OMe Cl Cl 456 Me CH(cBu)CH₂OMe Cl Cl 457 Me CH(nPr)CH₂OMe Cl Cl 458 Me CH(cPr)C₂H₄OMe Cl Cl 459 Me CH(cBu)C₂H₄OMe Cl Cl 460 Me CH(Et)C₂H₄OMe Cl Cl 461 Me CHEt₂ OMe Cl 462 Me CH(Et)CH₂OMe OMe Cl 463 Me CH(cPr)Et OMe Cl 464 Me CH(cPr)Me OMe Cl 465 Me CH(cPr)CH₂OMe OMe Cl 466 Me CH(cBu)CH₂OMe OMe Cl 467 Me CH(nPr)CH₂OMe OMe Cl 468 Me CH(cPr)C₂H₄OMe OMe Cl 469 Me CH(cBu)C₂H₄OMe OMe Cl 470 Me CH(Et)C₂H₄OMe OMe Cl 471 Me CHEt₂ Me Cl 472 Me CH(Et)CH₂OMe Me Cl 473 Me CH(cPr)Et Me Cl 474 Me CH(cPr)Me Me Cl 475 Me CH(cPr)CH₂OMe Me Cl 476 Me CH(cBu)CH₂OMe Me Cl 477 Me CH(nPr)CH₂OMe Me Cl 478 Me CH(cPr)C₂H₄OMe Me Cl 479 Me CH(cBu)C₂H₄OMe Me Cl 480 Me CH(Et)C₂H₄OMe Me Cl 481 Me CHEt₂ OMe Me 342 138-140° C. 482 Me CH(cPr)Et OMe Me 483 Me CH(Et)CH₂OMe OMe Me 484 Me CH(cPr)Me OMe Me 485 Me CH(cPr)CH₂OMe OMe Me 486 Me CH(cBu)CH₂OMe OMe Me 487 Me CH(nPr)CH₂OMe OMe Me 488 Me CH(cPr)C₂H₄OMe OMe Me 489 Me CH(cBu)C₂H₄OMe OMe Me 490 Me CH(Et)C₂H₄OMe OMe Me 491 Me CHEt₂ OMe Br 492 Me CH(cPr)Et OMe Br 493 Me CH(Et)CH₂OMe OMe Br 494 Me CH(cPr)Me OMe Br 495 Me CH(cPr)CH₂OMe OMe Br 496 Me CH(cBu)CH₂OMe OMe Br 497 Me CH(nPr)CH₂OMe OMe Br 498 Me CH(cPr)C₂H₄OMe OMe Br 499 Me CH(cBu)C₂H₄OMe OMe Br 500 Me CH(Et)C₂H₄OMe OMe Br 501 Cl CH(Et)Me OMe Cl 368.0927 502 Cl CH(Et)Me OMe Br 412.0448 503 Cl CH(Et)Me OMe Me 348.1490 504 Cl CH(Et)Me Cl Cl 372.0428 505 Br CH(Et)Me OMe Br 470.0084 506 Br CHEt₂ OMe Me 406.1125 507 Br CHEt₂ Cl Cl 430.0109 508 Cl CH(cPr)Et OMe Cl 394.1099 509 Cl CH(cPr)Et OMe Br 438.0570 510 Cl CH(cPr)Et OMe Me 374.1617 511 Cl CH(cPr)Et Cl Cl 398.0575 512 Cl CH(cPr)Et Br Br 485.9592 514 Cl CH(cPr)Et OMe Cl 394.1088 515 Cl CH(cPr)Et OMe Br 438.0605 516 Cl CH(cPr)Et OMe Me 374.1634 517 Cl CH(cPr)Et Cl Cl 398.0602 518 Cl CH(cPr)Et Br Br 485.9604 520 Cl CH(Me)CH₂OMe Cl Cl 388.0358 521 Cl CH(Me)CH₂OMe Br Br 474.9285 523 Cl CH(Et)CH₂OMe OMe Br 442.0532 524 Cl CH(Et)CH₂OMe Cl Cl 402.0568 525 Br CH(Et)CH₂OMe OMe Br 486.0018 526 Br CH(Et)CH₂OMe OMe Me 422.1097 527 Br CH(Et)CH₂OMe Cl Cl 446.0008 529 Cl CH(Et)CH₂OMe OMe Br 442.0516 530 Cl CH(Et)CH₂OMe Cl Cl 402.0520 531 Br CH(Et)CH₂OMe Cl Cl 446.0050 532 Cl CH(CH(Me)CH₃)₂ OMe Me 390.1958 533 Cl CH₂(CH₂CH₂SMe) OMe Br 428.9899 534 Cl CH₂(CH₂CH₂SMe) OMe Me 365.0967 535 Cl CH₂(CH₂CH₂SMe) Cl Cl 388.9920 538 Cl CH(Et)Me Br Cl 415.9943 539 Et CHEt₂ Cl Cl 380.1280 540 Cl CHEt₂ Br Cl 430.0106 541 —CN CHEt₂ Cl Cl 377.0910 542 Cl (1R)-CH(cPr)Et Br Cl 442.0102 543 Cl (1S)-CH(cPr)Et Br Cl 442.0093 544 Cl CH(Et)CH₂OMe OMe Cl 398.1064 545 Cl CH(Et)CH₂OMe OMe Me 378.1604 546 Cl CH(Et)CH₂OMe OMe CN 388.1298 547 Br (1R)-CH(Et)CH₂OMe Br Cl 489.9534 548 Cl (1S)-CH(Et)CH₂OMe Br Cl 446.0048 549 Br CH(Et)CH₂OMe OMe Me 422.1096 557 Cl CH(cBu)Et OMe Cl 480.1270

TABLE 2A

Mass Spec Ex. # R¹ R³ R⁴ R⁵ R^(5a) (M + H) 513 Cl (1R)-CH(cPr)Et OMe Cl F 412.1019 519 Cl (1S)-CH(cPr)Et OMe Cl F 412.1001 522 Cl CH(Et)CH₂OMe OMe Cl F 416.0955 528 Br CH(Et)CH₂OMe OMe Cl F 460.0460

TABLE 2B

Mass Spec Ex. # R¹ R² R³ R⁴ R⁵ (M + H) 536 Cl Me CH(Et)₂ OMe Cl 396.1259 537 Cl Me CH(cBu)Et OMe Cl 422.1420

TABLE 3

Mass Spec Ex. # R¹ R³ R⁴ R⁵ (M + H) 550 Cl CH(Et)₂ OMe Br 440.0750 551 Cl (1R)-CH(cPr)Et OMe Br 452.0766 552 Cl (1S)-CH(cPr)Et OMe Br 452.0734 553 Cl CH(Me)CH₂OMe OMe Br 442.0557 554 Br CH(Et)CH₂OMe OMe Br 500.0205 555 Cl CH(Et)CH₂OMe OMe Br 456.0670

TABLE 4

Ex. # R¹ R³ R⁴ R⁵ Mass Spec 556 Cl (1R)-CH(cPr)Et OMe Br 453.0459 558 Cl CH(cBu)Et OMe Br 468.0665 559 Cl CH(cBu)Et OMe Cl 424.1199 560 Cl (1S)-CH(cPr)Et OMe Br 454.0518 561 Cl (1R)-CH(Et)CH₂OMe OMe Br 457.0410 562 Cl (1S)-CH(Et)CH₂OMe OMe Br 458.0457 563 Cl (1S)-CH(Me)CH₂OMe OMe Br 444.0339 564 Cl CH(cBu)Et OMe H 390.1595 565 Cl (1R)-CH(cPr)Et OMe H 376.1452 566 Br (1R)-CH(Et)CH₂OMe OMe Br 501.9992

Also provided herein are pharmaceutical compositions comprising compounds of this invention and a pharmaceutically acceptable carrier, which are media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.

This invention thus further provides a method of treating a subject afflicted with a disorder characterized by CRF overexpression, such as those described hereinabove, which comprises administering to the subject a pharmaceutical composition provided herein. Such compositions generally comprise a therapeutically effective amount of a compound provided herein, that is, an amount effective to ameliorate, lessen or inhibit disorders characterized by CRF overexpression. Such amounts typically comprise from about 0.1 to about 1000 mg of the compound per kg of body weight of the subject to which the composition is administered. Therapeutically effective amounts can be administered according to any dosing regimen satisfactory to those of ordinary skill in the art.

Administration is, for example, by various parenteral means. Pharmaceutical compositions suitable for parenteral administration include various aqueous media such as aqueous dextrose and saline solutions; glycol solutions are also useful carriers, and preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents; also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Alternatively, compositions can be administered orally in solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, stearic acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

This invention is described in the following examples, which those of ordinary skill in the art will readily understand are not limiting on the invention as defined in the claims which follow thereafter.

EXAMPLES Example 1 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine

Part A: A solution of 4,6-dichloro-2-methylpyrimidine (5 g, 30.70 mmol), 3-pentylamine (5.5 mL, 46.90 mmol) and diisopropylethyl amine (5.5 mL, 31.60 mmol) were heated at reflux in ethanol (40 mL) for 7 h. The reaction was partitioned between EtOAc (250 mL) and water (30 mL), and the EtOAc was washed with water, brine, dried and stripped in vacuo to give 7 g crude product, which was used in the next reaction without further purification.

Part B: A solution of 4-chloro-6-(1-ethylpropylamino)-2-methylpyrimidine (2.1 g, 10 mmol) and 5,7-dichloroindoline (2 g, 10.6 mmol) were heated at 190° C. in ethylene glycol (16 mL) for 4 h. The reaction mixture was partitioned between EtOAc (100 mL) and 0.5 N NaOH (50 mL) and the aqueous layer was extracted with EtOAc (100 mL), and the combined organic extracts were washed with water, brine, dried and stripped in vacuo. The residue was chromatographed on silica gel (30% EtOAc/hexanes, followed by 50% EtOAc/hexanes eluent) to give the product, which was crystallized from ether/hexanes (2.1 g, 57% yield).

Example 2 5-chloro-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (140 mg, 0.38 mmol) and N-chlorosuccinimide (60 mg, 0.45 mmol) were stirred in dry acetonitrile (5 mL) at 20° C. for 20 h. The reaction mixture was stripped in vacuo and the residue was chromatographed on silica gel using 20% EtOAc/hexanes to give the product, 5-chloro-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (150 mg, 99% yield).

Example 3 5-bromo-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.15 g, 3.14 mmol) and pyridinium tribromide (1.16 g, 3.63 mmol) were stirred in dry dichloromethane (20 mL) at 20° C. for 16 h. The reaction mixture was quenched with saturated aqueous Na₂S₂O₅ (6 mL) and diluted with EtOAc (200 mL). The EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes to give the product, 5-bromo-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.30 g, 93% yield).

Example 4 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-iodo-2-methylpyrimidine

4-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine, (365 mg, 1 mmol) was stirred in a two phase mixture of water (20 mL) and CH₂Cl₂ (2 mL) with NaHCO₃ (110 mg, 1.3 mmol) and 12 (304 mg, 1.2 mmol) at 20° C. for 16 h. The reaction was quenched with saturated Na₂S₂O₅ (5 mL) and extracted with EtOAc (100 mL). The EtOAc was washed with brine, dried over (MgSO₄) and stripped in vacuo to give the title compound. The crude product can be used in the next reaction without further purification.

Example 5 5-cyano-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine

4-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-iodo-2-methylpyrimidine (450 mg, 0.92 mmol) was heated at 140° C. in 5 mL DMF with CuCN (111 mg, 1.23 mmol) and NaCN (84 mg, 1.70 mmol) for 6 h. The reaction was poured into 20 mL 9:1 NH₄Cl/NH₄OH and stirred for 20 min. The product was extracted with EtOAc (100 mL) and the EtOAc was washed with water (20 mL), brine, dried over (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes as eluent to give the title compound 80 mg, mp 163-165° C.

Example 6 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine

To a suspension of AlCl₃ (736 mg, 5.44 mmol) in CHCl₃ (5 mL) a solution of 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.46 g, 4 mmol) in CHCl₃ was added at 0° C., followed by Cl₂CHOMe (0.4 mL, 4.4 mmol). The reaction was stirred at 0° C. for 2 h and at 20° C. for 16 h. Then an additional amount of Cl₂CHOMe was added (0.2 mL, 2.2 mmol) and the reaction was continued for 26 h. The mixture was poured into ice/water (50 mL) and after quenching it was basified with 1 N NaOH, extracted with EtOAc (2×100 mL each) and the combined organic extracts were washed with water, brine, dried over (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel using 10% EtOAc/hexanes as eluent to give the product 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine (470 mg, 30% yield).

Example 7 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-hydroxymethyl-2-methylpyrimidine

4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine, (50 mg, 0.13 mmol) was stirred with NaBH₄ (7 mg, 0.2 mmol) in dry ethanol (2 mL) at 0° C. for 2 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL) and the EtOAc was washed with brine, dried (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel using 40% EtOAc/hexanes to give the product, 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-hydroxymethyl-2-methylpyrimidine (40 mg, 80% yield).

Example 53 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine

Part A: A mixture of 7-chloro-5-methoxyindoline hydrochloride (4.45 g, 20.2 mmol) and anhydrous tetrahydrofuran (168 mL) was cooled to 0° C. while adding via syringe (1.0 M) sodium bis(trimethylsilyl)amide in tetrahydrofuran (39.0 mL, 39.0 mmol). Next was added portionwise 4,6-dichloro-2-methylpyrimidine (3.00 g, 18.4 mmol). The reaction mixture was kept cool at 0° C. for 1 hour. The bath was removed and allowed to warm to room temperature overnight. Another portion of sodium bis(trimethylsilyl)amide in tetrahydrofuran (9.2 mL, 9.2 mmol) was added and continued stirring for another 1.5 hours. One more portion of sodium bis(trimethylsilyl)amide in tetrahydrofuran (4.6 mL, 4.6 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was quenched with H₂O and extracted with ethyl acetate. Combined the organics and washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was chromatographed on silica gel using 20% ethyl acetate/hexanes as the eluent to afford a yellow solid (6.82 g). APCI-MS calcd for C₁₉H₂₅ClN₄O (360.17): (M+H)⁺=361.4, 100%; 363.5, 32%.

Part B: The product from part A (200 mg, 0.64 mmol) and 1-ethyl-propylamine (0.60 mL, 5.12 mmol) were stirred in a 80° C. oil bath over 7 days. The crude product was chromatographed on silica gel using a gradient from 40-50% ethyl acetate/hexanes as the eluent to afford the title compound (137 mg). Elemental analysis calcd for C₁₉H₂₅ClN₄O: C, 63.24; H, 6.98; N, 15.52. Found: C, 63.39; H, 7.06; N, 15.44.

Example 59 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-(1-ethylpropylamino)-2-methylpyrimidine

Part A: A mixture of 4,6-dichloro-2-methylpyrimidine (6.16 g, 37.8 mmol), 1-ethylpropyl-amine (6.6 mL, 56.7 mmol), N,N′-diisopropylamine (6.8 mL, 38.9 mmol), and ethanol (50 mL) were heated at reflux temperature for 7 hours. Water (80 mL) was added and extracted with ethyl acetate (400 mL). The organics were combined and washed with brine, dried over MgSO₄, filtered and concentrated to afford a white solid (8.24 g).

Part B: The product from part A (4.1 g, 19.2 mmol), 5-methoxy-7-chloro-indoline (3.7 g, 20.2 mmol) and ethylene glycol (20 mL) were heated to 190° C. for 11 hours. Aqueous 0.5 N NaOH solution (100 mL) was added and extracted with ethyl acetate. The organics were combined and washed with brine, dried over MgSO₄, filtered and concentrated. The crude oil was chromatographed on silica gel using a gradient from 30-50% ethyl acetate/hexanes as the eluent to afford a dark green foam. The product was rechromatographed using hexanes/ethyl acetate/methylene chloride (5:3:2 to 4:5:1) as the eluent to afford a dark green foam (3.60 g). APCI-MS calcd for C₁₉H₂₅ClN₄O (360.17): (M+H)⁺=361.1, 100%; 363.1, 39%.

Part C: The product from part B (3.60 g, 9.98 mmol) was dissolved in CH₂Cl₂ (4.0 mL) and H₂O (14.0 mL). Next was added NaHCO₃ (1.09 g, 12.97 mmol) followed by iodine (2.56 g, 10.08 mmol) at 10-15° C. The reaction mixture was allowed to warm to room temperature overnight. A saturated Na₂S₂O₅ solution (125 mL) was added and extracted with ethyl acetate. The organics were combined and washed with brine, dried over MgSO₄, filtered and concentrated. The crude solid was chromatographed on silica gel using a gradient from 10-20% ethyl acetate/hexanes as the eluent to afford a white solid (2.53 g).

Part D: The product from part C (2.53 g, 5.20 mmol), CuCN (0.61 g, 6.76 mmol), NaCN (0.46 g, 9.36 mmol), and anhydrous N,N-dimethylformamide (25.0 mL) were heated in a 140° C. oil bath overnight. Water was added and extracted with ethyl acetate. The organics were combined and washed with H₂O, brine, dried over MgSO₄, filtered and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexanes as the eluent to afford the title compound (1.91 g). mp 192-194° C. Elemental Analysis calcd for C₂₀H₂₄ClN₅O: C, 62.25; H, 6.278; N, 18.15. Found: C, 61.88; H, 6.18; N, 17.88.

Example 60 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine

Part A: The product from part D, Example 59 (100 mg, 0.26 mmol) was dissolved in anhydrous diethyl ether (3.0 mL) and cooled to −78° C. A solution of 1.0 M diisobutylaluminum hydride in hexanes (0.52 mL, 0.52 mmol) added slowly via syringe to the reaction mixture. The solution was allowed to warm to room temperature over 1.5 hours. Water and 1.0 M HCl solution (3 mL) were added. Stirred the reaction mixture for 30 minutes. The aqueous was made basic with a 1.0 N NaOH solution and extracted with diethyl ether. The organics were combined and washed with brine, dried over MgSO₄, filtered and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate as the eluent to afford a yellow solid (70 mg). The solids were recrystallized from ether/methylene chloride/hexanes to afford a yellow solid (21 mg). Again the product was chromatographed on silica gel using 30% diethyl ether/hexanes as the eluent to afford the title compound (11 mg). mp 178-179° C. ESI-HRMS calcd for C₂₀H₂₆ClN₄O₂ (M+H)⁺: 389.1745. Found: 389.1759.

Example 70 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine

The title compound was prepared by using similar procedures indicated in parts A and B of Example 59. APCI-MS calcd for C₁₉H₂₅C₁N₄O₂ (376.17): (M+H)⁺=377.2, 75%; 379.2, 29%.

Example 74 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-iodo-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine

The title compound was prepared by using similar procedures indicated in parts A, B and C of Example 59. mp 150-152° C. APCI-MS calcd for C₁₉H₂₄ClIN₄O₂ (502.06): (M+H)⁺=503.0, 100.0%; 505.1, 35%.

Example 75 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine

The title compound was prepared in the similar manner to the procedure in Example 59. mp 182-183° C. Elemental Analysis calcd for C₂₀H₂₄ClN₅O₂: C, 59.77; H, 6.029; N, 17.43. Found: C, 59.40; H, 6.00; N, 17.13.

Example 76 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-formyl-6-[1-(1-methoxymethyl)propylamino]-2-methylpyrimidine

The title compound was prepared in the similar manner to the product in Example 60. mp 150-153° C. Elemental Analysis calcd for C₂₀H₂₅ClN₄O₃: C, 59.33; H, 6.22; N, 13.84. Found: C, 59.34; H, 6.35; N, 13.59.

Example 86 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-ethyl-3-methoxy)propylamino]-2-methylpyrimidine

The title compound was prepared by using similar procedures indicated in part A and B of Example 59. APCI-MS calcd for C₂₀H₂₇ClN₄O₂ (390.18): (M+H)⁺=391.2, 100%; 393.2, 33%.

Example 91 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-ethyl-3-methoxy)propylamino]-5-iodo-2-methylpyrimidine

The product from Example 86 (1.97 g, 5.04 mmol), sodium bicarbonate (0.55 g, 6.55 mmol), water (7 mL), and methylene chloride (2 mL) were stirred and cooled to 10-15° C. Slowly added iodine (1.29 g, 5.09 mmol) portionwise. Allowed the reaction mixture to warm up slowly to room temperature. Stirred for two days. Added a solution of sodium metabisulfite and ethyl acetate. Stirred for 10 minutes. Separated the layers and extracted the water layer with ethyl acetate (2×). Combined the organics and washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was chromatographed on silica gel using 10% ethyl acetate/hexanes as the eluent to afford the title compound (939 mg). mp 127-128° C. Elemental analysis calcd for C₂₀H₂₆ClIN₄O₂: C, 46.48; H, 5.07; N, 10.84. Found: C, 46.56; H, 5.02; N, 10.66.

Example 92 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-cyano-6-[1-(1-ethyl-3-methoxy)propylamino]-2-methylpyrimidine

The product from part A, Example 91 (912 mg, 1.76 mmol), copper(I) cyanide (205 mg, 2.29 mmol), sodium cyanide (155 mg, 3.17 mmol), and anhydrous dimethylforamide (11 mL) were stirred in a 140° C. oil bath overnight. The reaction mixture was partitioned between ethyl acetate and water. Extracted the aqueous layer with ethyl acetate (2×). Combined the organics and washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was chromatographed on silica gel using 30% ethyl acetate/hexanes as the eluent to afford the title compound (156 mg). mp 137-139° C. Elemental analysis calcd for C₂₁H₂₆ClN₅O₂: C, 60.64; H, 6.30; N, 16.84. Found: C, 60.85; H, 6.30; N, 16.71.

The enantiomers of Example 92 were isolated using the following conditions: COLN: AD @ 27 C using diethylamine/isopropanol/hexanes (1/100/900) 1.5 mL/min, 260 NM. Collection #1: 39.2 mg, EE=>99%, collection #2: 36.8 mg, EE=>99% to afford the pure enantiomers: [a]_(D) ²³−10.8° (c 0.196, CHCl₃); [a]_(D) ²³+9.8°, (c=0.190, CHCl₃).

Example 309 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-methylbutylamino)-2-methylpyrimidine

Part A: The product from part A, Example 53 (200 mg, 0.64 mmol) and 2-aminopentane (0.45 g, 5.12 mmol) were stirred in a 80° C. oil bath overnight. The crude product was chromatographed on silica gel using a gradient from 40-50% ethyl acetate/hexanes as the eluent to afford the title compound (187 mg). Elemental analysis calcd for C₁₉H₂₅ClN₄O: C, 63.24; H, 6.98; N, 15.52. Found: C, 62.92; H, 7.03; N, 15.54.

Example 310 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-(1-methylpropylamino)-2-methylpyrimidine

Part A: The product from part A, Example 53 (400 mg, 1.29 mmol), 2-butylamine (0.13 mL, 1.29 mmol) and ethanol (3 mL) were heated at reflux temperature for approximately 7 hours. The reaction mixture was concentrated. The crude product was chromatographed on silica gel using a gradient from 40-50% ethyl acetate/hexanes as the eluent to afford the title compound (309 mg). mp 102-105° C. Elemental Analysis calcd for C₁₈H₂₃ClN₄O: C, 62.33; H, 6.68; N, 16.15. Found: C, 62.50; H, 6.77; N, 16.04.

Example 311 4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-6-[1-(1-cyclobutyl)ethylamino)-2-methylpyrimidine

Part A: The product from part A, Example 53 (200 mg, 0.64 mmol), 2-amino(1-methyl)cyclopropane hydrochloride (0.34 g, 2.56 mmol), N,N′-diisopropylethylamine (0.83 mL, 4.76 mmol), and anhydrous CH₃CN (0.5 mL) were stirred in a 80° C. oil bath over 7 days. Water was added and extracted with ethyl acetate. The organics were combined and washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was chromatographed on silica gel to afford the title compound (0.47 mg). mp 125-128° C.

Example 401 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 168-170° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.78 (s, 1 H), 4.82-4.78 (m, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 1.88-1.74 (m, 2 H), 1.70-1.60 (m, 2 H), 0.88 (t, J=7.5 Hz, 6 H); HRMS (ESI) calcd for C₁₇H₁₉N₃OCl₃ (M+H)⁺: 386.0594; found m/z 386.0614.

Example 402 5-Chloro-1-(1-cyclopropylpropyl)-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.32 (1H, m), 0.51 (2H, m), 0.78 (1H, m), 0.94 (3H, t, J=7.4 Hz), 1.05 (1H, m), 1.86 (2H, m), 3.13 (2H, t, J=7.9 Hz), 4.06 (1H, m), 4.33 (2H, t, J=7.9 Hz), 7.00 (1H, s), 7.10 (1H, d, J=1.9 Hz), 7.17 (1H, d, J=1.8 Hz). MS (APCI+) m/z 398 (M+H)⁺.

Example 404 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.5 Hz), 1.83 (2H, m), 3.12 (2H, t, J=8.1 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 4.34 (2H, t, J=7.9 Hz), 4.93 (1H, m), 7.05 (1H, s), 7.10 (1H, d, J=1.9 Hz), 7.17 (1H, d, J=1.8 Hz). MS (APCI+) m/z 402 (M+H)⁺.

Example 410 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 95-97° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, J=2.2 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.78 (s, 1 H), 4.89-4.82 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.39-3.27 (m, 2 H), 3.25 (s, 3 H), 3.11 (t, J=7.9 Hz, 2 H), 2.01-1.93 (m, 2 H), 1.84-1.72 (m, 2 H), 0.86 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₁N₃O₂Cl₃ (M+H)⁺: 416.0699; found m/z 416.0717.

Example 413 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

To 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (1.0 g), prepared as described in Scheme 4, and 7-chloro-5-methoxyindoline hydrochloride (0.92 g), prepared as described in U.S. Pat. No. 6,245,769, stirring in anhydrous tetrahydrofuran (25 mL, 0° C.) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11.9 mL, dropwise). The reaction mixture was allowed to come to ambient temperature and stirred 18 hours. Water was added, and the mixture was extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO₄, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (329 mg). mp 131-133° C. ¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.3 Hz), 1.83 (2H, m), 3.09 (2H, t, J=7.6 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 3.78 (3H, s), 4.34 (2H, t, J=7.7 Hz), 4.94 (1H, m), 6.74 (2H, s), 6.99 (1H, s). MS (APCI+) m/z 398 (M+H)⁺.

Example 420 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=7.4 Hz), 1.80 (2H, m), 2.00 (2H, m), 3.10 (2H, t, J=7.7 Hz), 3.28 (3H, s), 3.34 (2H, m), 3.78 (3H, s), 4.35 (2H, t, J=7.9 Hz), 4.85 (1H, br), 6.74 (3H, s). MS (APCI+) m/z 412 (M+H)⁺.

Example 431 5-Chloro-1-(1-ethylpropyl)-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 164-165° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.67 (s, 1H), 6.66 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.82-4.80 (m, 1 H), 4.39 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.84-1.73 (m, 2 H), 1.70-1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C₁₉H₂₅N₃O₂Cl (M+H)⁺: 362.1635; found m/z 362.1648.

Example 433 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.5 Hz), 1.82 (2H, m), 2.06 (3H, s), 3.04 (2H, t, J=7.7 Hz), 3.36 (3H, s), 3.56 (1H, dd), 3.66 (1H, dd), 3.79 (3H, s), 4.38 (2H, t, J=7.7 Hz), 4.97 (1H, m), 6.59 (1H, s), 6.67 (1H, s), 6.92 (1H, s). MS (APCI+) m/z 378 (M+H)⁺.

Example 440 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=7.4 Hz), 1.80 (2H, m), 1.98 (2H, M), 2.06 (3H, s), 3.04 (2H, t, J=7.7 Hz), 3.29 (3H, s), 3.35 (2H, m), 3.79 (3H, s), 4.38 (2H, t, J=7.7 Hz), 4.89 (1H, br), 6.48 (1H, s), 6.60 (1H, s), 6.63 (1H, s). MS (APCI+) m/z 392 (M+H)⁺.

Example 441 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 130-132° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.92 (d, J=2.6 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 6.73 (s, 1 H), 4.81 (brs, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (s, 6 H); HRMS (ESI) calcd for C₁₈H₂₂N₃O₂BrCl (M+H)⁺: 426.0584; found m/z 426.0606.

Example 443 5-Chloro-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.82 (2H, m), 3.10 (2H, t, J=7.6 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 3.78 (3H, s), 4.35 (2H, t, J=7.9 Hz), 4.95 (1H, m), 6.78 (1H, d, J=2.2 Hz), 6.92 (1H, d, J=2.5 Hz), 7.00 (1H, s). MS (APCI+) m/z 442 (M+H)⁺.

Example 450 5-Chloro-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 413. ¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=7.4 Hz), 1.80 (2H, m), 2.00 (2H, m), 3.11 (2H, t, J=7.7 Hz), 3.28 (3H, s), 3.34 (2H, m), 3.78 (3H, s), 4.35 (2H, t, J=7.9 Hz), 4.85 (1H, br), 6.75 (1H, s), 6.78 (1H, d, J=2.2 Hz), 6.92 (1H, d, J=2.2 Hz). MS (ESI+) m/z 454 (M+H)⁺.

Example 451 3-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone

Prepared in a similar fashion as described for XXXII (Example 481, Part B) using 5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) as the starting material. mp 137-139° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.14 (d, J=1.8 Hz, 1 H), 7.09 (d, J=2.2 Hz, 1 H), 6.54 (s, 1 H), 4.82 (brs, 1 H), 4.31 (t, J=8.1 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 2.16 (s, 3 H), 1.83-1.74 (m, 2 H), 1.68-1.60 (m, 2 H), 0.86 (t, J=7.4 Hz, 6 H); HRMS (ESI) calcd for C₁₈H₂₂N₃OCl₂ (M+H)⁺: 366.1140; found m/z 366.1156.

Example 481 3-(5-Methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone

Part A. Preparation of 5-bromo-1-(1-ethylpropyl)-3-(methylthio)-2(1H)-pyrazinone (XXXI).

A solution of 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone (XXX) (3.23 g, 10 mmol), prepared using the conditions described in U.S. Pat. No. 6,159,980 (Example 84, Part A), hereby incorporated by reference, and sodium thiomethoxide (701 mg, 10 mmol) in THF (50 mL) was stirred at 25° C. for 72 h. The reaction mixture was diluted with water (75 mL) and ethyl acetate (75 mL). The organic phase was dried over (MgSO₄), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:4) gave the product XXXI (2.30 g, 82%) as a white solid.

Part B. Preparation of 1-(1-Ethylpropyl)-5-methyl-3-(methylthio)-2(1H)-pyrazinone (XXXII).

A solution of XXXI (2.0 g, 6.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) (484 mg, 0.7 mmol) in THF (40 mL) was treated with trimethylaluminum (6.2 mL, 12.4 mmol, 2M/toluene) dropwise at 0° C. The reaction was refluxed for 4 h, cooled to 0° C. quenched with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:1) gave the product XXXII (1.14 g, 73%) as a pale yellow solid.

Part C. Preparation of 1-(1-Ethylpropyl)-5-methyl-3-(methylsulfonyl)-2(1H)-pyrazinone (XXXIII).

A solution of XXXII (200 mg, 0.9 mmol) in THF (25 mL) was treated with Oxone™ (1.1 g, 1.8 mmol) portionwise as a solid at 25° C. The reaction mixture was stirred at 25° C. for 16 h and diluted with water (20 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to give the product XXXIII (153 mg, 67%) as a yellow oil.

Part D. Preparation of 3-(5-Methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone (481)

Example 481 was prepared in a similar fashion as described for Example 413 using XXXIII and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 138-140° C.; ¹H NMR (300 MHz, CDCl₃) δ 6.68 (d, J=2.2 Hz, 1 H), 6.56 (d, J=2.2 Hz, 1 H), 6.44 (s, 1 H), 4.90-4.79 (brs, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.9 Hz, 2 H), 2.11 (s, 3 H), 2.00 (s, 3 H), 1.82-1.71 (m, 2 H), 1.67-1.60 (m, 2 H), 0.87 (t, J=7.4 Hz, 6 H); HRMS (ESI) calcd for C₂₀H₂₈N₃O₂ (M+H)⁺: 342.2182; found m/z 342.2196.

Example 501 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-methylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 143-145° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.89 (s, 1 H), 6.77-6.72 (m, 2 H), 4.96-4.89 (m, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.76 (s, 3 H), 3.07 (t, J=7.7 Hz, 2 H), 1.74-1.64 (m, 2 H), 1.33 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.6 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₂₀N₃O₂Cl₂ (M+H)⁺: 368.0933; found m/z 368.0927.

Example 502 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-methylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 155-157° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.90 (d, J=2.6 Hz, 1 H), 6.78 (s, 1 H), 6.76 (d, J=2.1 Hz, 1H), 4.99-4.87 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.74-1.65 (m, 2 H), 1.34 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.5 Hz, 3H); HRMS (ESI) calcd for C₂₀H₂₂N₃O₂BrCl (M+H)⁺: 412.0427; found m/z 412.0448.

Example 503 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-methylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 176-178° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.70 (s, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.57 (d, J=2.2 Hz, 1 3H), 4.98-4.91 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.77 (s, 3 H), 3.02 (t, J=7.7 Hz, 2 H), 2.04 (s, 3 H), 1.74-1.64 (m, 2 H), 1.33 (d, J=6.9 Hz, 3 H), 0.90 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₃N₃O₂Cl (M+H)⁺: 348.1479; found m/z 348.1490.

Example 504 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-1-(1-methylpropyl)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 177-178° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, J=1.9 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.83 (s, 1 H), 4.98-4.86 (m, 1 H), 4.33 (t, J=8.1 Hz, 2 H), 3.11 (t, J=7.9 Hz, 2 H), 1.75-1.65 (m, 2 H), 1.34 (d, J=6.6 Hz, 3 H), 0.89 (t, J=7.4 Hz, 3H); HRMS (ESI) calcd for C₁₆H₁₇N₃OCl₃ (M+H)⁺: 372.0437; found m/z 372.0428.

Example 505 5-Bromo-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 133-135° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.92 (d, J=2.6 Hz, 1 H), 6.81 (s, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.81-4.78 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C₁₈H₂₂N₃O₂Br₂ (M+H)⁺: 470.0079; found m/z 470.0084.

Example 506 5-Bromo-1-(1-ethylpropyl)-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 152-154° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.73 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=1.9 Hz, 1 H), 4.84-4.76 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.87-1.73 (m, 2 H), 1.70-1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C₁₉H₂₅N₃O₂Br (M+H)⁺: 406.1130; found m/z 406.1125.

Example 507 5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 158-160° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.85 (s, 1 H), 4.80-4.75 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=8.1 Hz, 2 H), 1.88-1.74 (m, 2 H), 1.70-1.60 (m, 2 H), 0.88 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C₁₇H₁₉N₃OBrCl₂ (M+H)⁺: 430.0089; found m/z 430.0109.

Example 508 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 118-120° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34-4.24 (m, 2 H), 4.09-4.01 (m, 1 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.93-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.81 (m, 3 H), 0.79-0.72 (m, 1 H), 0.54-0.44 (m, 2 H), 0.34-0.22 (m, 1 H); HRMS (ESI) calcd for C₁₉H₂₂N₃O₂Cl₂ (M+H)⁺: 394.1089; found m/z 394.1099.

Example 509 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138-140° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1H), 6.75 (d, J=2.5 Hz, 1 H), 4.34-4.24 (m, 2 H), 4.10-4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.91-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.86 (m, 3 H), 0.79-0.72 (m, 1 H), 0.53-0.44 (m, 2 H), 0.35-0.24 (m, 1 H); HRMS (CI) calcd for C₁₉H₂₂N₃O₂BrCl (M+H)⁺: 438.0584; found m/z 438.0570.

Example 510 5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 160-162° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.89 (s, 1 H), 6.67 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz, 1 H), 4.37 (t, J=7.7 Hz, 2H), 4.29-4.04 (m, 1 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.07 (s, 3 H), 1.95-1.75 (m, 2 H), 1.08-1.00 (m, 1 H), 0.95 (t, J=7.5 Hz, 3 H), 0.82-0.75 (m, 1 H), 0.57-0.47 (m, 2 H), 0.36-0.29 (m, 1 H); HRMS (ESI) calcd for C₂₀H₂₅N₃O₂Cl (M+H)⁺: 374.1635; found m/z 374.1617.

Example 511 5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 166-168° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34-4.24 (m, 2 H), 4.08-3.99 (m, 1 H), 3.11 (t, J=8.1 Hz, 2H), 2.12-2.05 (m, 1 H), 1.92-1.76 (m, 1 H), 1.05-1.00 (m, 1 H), 0.94-0.86 (m, 3 H), 0.80-0.71 (m, 1 H), 0.53-0.46 (m, 2 H), 0.33-0.21 (m, 1 H); HRMS (ESI) calcd for C₁₈H₁₉N₃OCl₃ (M+H)⁺: 398.0594; found m/z 398.0575.

Example 512 5-Chloro-1-[(1R)-1-cyclopropylpropyl]-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Part A: Indoline (2.2 g, 18.04 mmol), dissolved in dichloromethane (160 mL) was stirred with pyridinium tribromide (12 g, 37.6 mmol) for 16 h at 25° C. The reaction was quenched with sat NaHSO₃ (50 mL) and water (50 mL). The dichloromethane was separated, dried (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 5,7-dibromoindoline (4.2 g, 84% yield). ¹H NMR(CDCl₃) δ 7.28 (m, 1H), 7.11 (s, 1H), 3.96 (s br, 1H), 3.63 (t J=9 Hz, 1H), 3.13 (t J=9 Hz, 2H).

Part B: Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 164-165° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.42 (d, J=1.8 Hz, 1 H), 7.22 (d, J=1.5 Hz, 1 H), 6.96 (s, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.99 (app. q, J=8.3 Hz, 1 H), 3.08 (t, J=7.9 Hz, 2 H), 1.94-1.69 (m, 2 H), 1.02-0.92 (m, 1 H), 0.87 (t, J=7.5 Hz, 3 H), 0.78-0.68 (m, 1 H), 0.50-0.39 (m, 2 H), 0.29-0.22 (m, 1 H); HRMS (ESI) calcd for C₁₈H₁₉N₃OBr₂Cl (M+H)⁺: 485.9583; found m/z 485.9592.

Example 513 5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 128-130° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2H), 4.08-4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.07-0.97 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.27 (m, 1H); HRMS (ESI) calcd for C₁₉H₂₁N₃O₂Cl₂F (M+H)⁺: 412.0995; found m/z 412.1019.

Example 514 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 128-130° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34-4.24 (m, 2H), 4.11-3.99 (m, 1 H), 3.75 (s, 3 H), 3.08 (t, J=7.9 Hz, 2 H), 1.93-1.73 (m, 2 H), 1.06-0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.79-0.72 (m, 1 H), 0.54-0.43 (m, 2 H), 0.34-0.24 (m, 1 H); HRMS (ESI) calcd for C₁₉H₂₂N₃O₂Cl₂ (M+H)⁺: 394.1089; found m/z 394.1088.

Example 515 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138-140° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1 H), 6.76 (d, J=2.2 Hz, 1 H), 4.34-4.24 (m, 2 H), 4.10-4.01 (m, 1H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.86 (m, 3 H), 0.79-0.72 (m, 1 H), 0.54-0.44 (m, 2 H), 0.35-0.22 (m, 1 H); HRMS (ESI) calcd for C₁₉H₂₂N₃O₂BrCl (M+H)⁺: 438.0584; found m/z 438.0605.

Example 516 5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 156-158° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.87 (s, 1 H), 6.65 (d, J=1.8 Hz, 1 H), 6.57 (d, J=2.2 Hz, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 4.10-4.02 (m, 1 H), 3.77 (s, 3 H), 3.02 (t, J=7.7 Hz, 2 H), 2.05 (s, 3 H), 1.93-1.73 (m, 2 H), 1.06-0.99 (m, 1 H), 0.95-0.87 (m, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.23 (m, 1 H); HRMS (ESI) calcd for C₂₀H₂₅N₃O₂Cl (M+H)⁺: 374.1635; found m/z 374.1634.

Example 517 5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 157-159° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34-4.24 (m, 2 H), 4.08-3.99 (m, 0.5 H), 3.11 (t, J=7.9 Hz, 2 H), 2.42-2.36 (m, 0.5 H), 2.16-2.00 (m, 1 H), 1.94-1.74 (m, 1 H), 1.07-0.99 (m, 1 H), 0.94-0.86 (m, 3 H), 0.80-0.71 (m, 1 H), 0.53-0.42 (m, 2 H), 0.36-0.20 (m, 1 H); HRMS (ESI) calcd for C₁₈H₁₉N₃OCl₃ (M+H)⁺: 398.0594; found m/z 398.0602.

Example 518 5-Chloro-1-[(1S)-1-cyclopropylpropyl]-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 165° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J=1.8 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.02 (s, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 4.06 (app. q, J=8.0 Hz, 1 H), 3.15 (t, J=8.1 Hz, 2 H), 1.99-1.74 (m, 2 H), 1.11-0.99 (m, 1 H), 0.94 (t, J=7.5 Hz, 3 H), 0.88-0.73 (m, 1 H), 0.57-0.46 (m, 2 H), 0.39-0.27 (m, 1 H); HRMS (CI) calcd for C₁₈H₁₉N₃OBr₂Cl (M+H)⁺: 485.9583; found m/z 485.9604.

Example 519 5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 127-129° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 4.11-4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.07-0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.25 (m, 1 H); HRMS (ESI) calcd for C₁₉H₂₁N₃O₂Cl₂F (M+H)⁺: 412.0995; found m/z 412.1001.

Example 520 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 93-95° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.18 (s, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.62-3.56 (m, 3 H), 3.36 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 0.90-0.86 (m, 3 H); HRMS (ESI) calcd for C₁₆H₁₇N₃O₂Cl₃ (M+H)⁺: 388.0386; found m/z 388.0358.

Example 521 5-Chloro-3-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 119-120° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, J=1.8 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.06 (s, 1 H), 5.14-5.09 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.62-3.52 (m, 2 H), 3.34 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.40 (d, J=7.0 Hz, 3 H); HRMS (CI) calcd for C₁₆H₁₆N₃O₂Br₂Cl (M+H)⁺: 474.9298; found m/z 474.9285.

Example 522 5-Chloro-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 140-142° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.00 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.97-4.85 (m, 1 H), 4.34 (t, J=7.6 Hz, 2 H), 3.86 (s, 3 H), 3.65 (dd, J=10.6, 5.8 Hz, 1 H), 3.54 (dd, J=10.6, 3.7 Hz, 1 H), 3.33 (s, 3 H), 3.07 (t, J=7.5 Hz, 2 H), 1.90-1.72 (m, 2 H), 0.92 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₁N₃O₃Cl₂F (M+H)⁺: 416.0944; found m/z 416.0955.

Example 523 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 102-104° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.99-4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (CI) calcd for C₁₈H₂₂N₃O₃BrCl (M+H)⁺: 442.0533; found m/z 442.0532.

Example 524 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143-146° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.15 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 7.03 (s, 1H), 4.94-4.90 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.7, 3.3 Hz, 1H), 3.33 (s, 3 H), 3.10 (t, J=8.1 Hz, 2 H), 1.88-1.70 (m, 2 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂Cl₃ (M+H)⁺: 402.0543; found m/z 402.0568.

Example 525 5-Bromo-3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 122-123° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.07 (s, 1 H), 6.92 (d, J=2.6 Hz, 1 H), 6.77 (d, J=2.2 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.66 (dd, J=10.7, 5.5 Hz, 1 H), 3.56 (dd, J=10.3, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.87-1.74 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₂N₃O₃Br₂ (M+H)⁺: 486.0028; found m/z 486.0018.

Example 526 5-Bromo-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 116-118° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.98 (s, 1 H), 6.67 (s, 1 H), 6.58 (d, J=2.2 Hz, 1 H), 4.97-4.95 (m, 1 H), 4.38 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.6, 5.9 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.9 Hz, 2 H), 2.06 (s, 3 H), 1.92-1.72 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₉H₂₅N₃O₃Br (M+H)⁺: 422.1079; found m/z 422.1097.

Example 527 5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 150-152° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.18 (d, J=2.2 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.95-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.55 (dd, J=10.6, 3.5 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂BrCl₂ (M+H)⁺: 446.0038; found m/z 446.0008.

Example 528 5-Bromo-3-(7-chloro-6-fluoro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 150-152° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.09 (s, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 4.95-4.90 (m, 1 H), 4.35 (t, J=8.1 Hz, 2 H), 3.89 (s, 3 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.36 (s, 3 H), 3.09 (t, J=8.4 Hz, 2 H), 1.96-1.77 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₁N₃O₃BrClF (M+H)⁺: 460.0439; found m/z 460.0460.

Example 529 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 100-102° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.6 Hz, 1 H), 4.99-4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₂N₃O₃BrCl (M+H)⁺: 442.0533; found m/z 442.0516.

Example 530 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143-146° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, J=1.9 Hz, 1 H), 7.09 (d, J=1.9 Hz, 1 H), 7.03 (s, 1H), 4.93-4.88 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.6, 3.5 Hz, 1H), 3.33 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.90-1.70 (m, 2 H), 0.91 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂Cl₃ (M+H)⁺: 402.0543; found m/z 402.0520.

Example 531 5-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 152-154° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.18 (d, J=1.9 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.93-4.89 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂BrCl₂ (M+H)⁺: 446.0038; found m/z 446.0050.

Example 532 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[2-methyl-1-(1-methylethyl)propyl)]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-isopropyl-2-methylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 94-96° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.70 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.73 (t, J=7.7 Hz, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.22-2.14 (m, 2 H), 2.05 (s, 3 H), 1.00 (d, J=7.0 Hz, 6H), 0.90 (d, J=7.0 Hz, 6 H); HRMS (ESI) calcd for C₂₁H₂₉N₃O₂Cl (M+H)⁺: 390.1948; found m/z 390.1958.

Example 533 3-(7-Bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. ¹H NMR (300 MHz, CDCl₃): δ 6.93 (d, J=2.5 Hz, 1 H), 6.88 (s, 1 H), 6.79 (d, J=2.5 Hz, 1H), 4.36 (t, J=7.7 Hz, 2 H), 4.05 (t, J=7.0 Hz, 2 H), 3.78 (s, 3 H), 3.10 (t, J=7.5 Hz, 2 H), 2.90 (t, J=7.0 Hz, 2 H), 2.17 (s, 3 H); HRMS (CI) calcd for C₁₆H₁₇N₃O₂SBrCl (M+): 428.9913; found m/z 428.9899.

Example 534 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 111-113° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.80 (s, 1 H), 6.68 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.40 (t, J=7.7 Hz, 2 H), 4.04 (t, J=7.1 Hz, 2 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.89 (t, J=7.2 Hz, 2 H), 2.18 (s, 3 H), 2.06 (s, 3 H); HRMS (CI) calcd for C₁₇H₂₀N₃O₂SCl (M+): 365.0965; found m/z 365.0967.

Example 535 5-Chloro-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 127-128° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.19 (d, J=1.8 Hz, 1 H), 7.12 (d, J=2.2 Hz, 1 H), 6.93 (s, 1H), 4.36 (t, J=8.1 Hz, 2 H), 4.06 (t, J=7.0 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 2.89 (t, J=7.0 Hz, 2 H), 2.16 (s, 3 H); HRMS (CI) calcd for C₁₅H₁₄N₃OSCl₃ (M+) 388.9923; found m/z 388.9920.

Example 536 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone

Part A: A solution of 1-ethylpropylamine (1.97 g, 22.6 mmol) in acetonitrile (50 mL) was treated with K₂CO₃ (9.3 g, 67.7 mmol) 2-bromopropionitrile (3.0 g, 22.6 mmol) and KI (4.13 g, 24.9 mmol). The mixture was heated at 55° C. for 20 h. The mixture was cooled to room temperature and was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (2% MeOH in CH₂Cl₂) to afford 2-(1-ethylpropylamino)-propionitrile (1.04 g, 36% yield) as a yellow oil.

-   Part B: A solution of 2-(1-ethylpropylamino)-propionitrile (1.0 g,     7.92 mmol) from Part A in toluene (36 mL) was treated with oxalyl     chloride (4.1 mL, 47.5 mmol) and the reaction mixture was heated at     50° C. for 20 h. The reaction mixture was cooled to room temperature     and concentrated. The residue was purified by column chromatography     on silica gel (10% EtOAc in hexanes→20% EtOAc in hexanes) to afford     3,5-dichloro-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone (696 mg,     35% yield) as a yellow amorphous solid: ¹H NMR (CDCl₃) δ 4.11-4.01     (m, 1 H), 2.50 (s, 3 H), 2.45-2.35 (m, 2 H), 1.98-1.82 (m, 2 H),     0.84 (t, J=7.5 Hz, 6 H); LRMS (APCI) m/z 248.9 [(M+H)⁺, calcd for     C₉H₁₃N₂OCl₂ 248.1].

Part C: A solution 3,5-dichloro-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone from Part B (80 mg, 0.321 mmol) and 7-chloro-5-methoxyindoline (61.9 mg, 0.337 mmol) in THF (1.6 mL) was cooled to 0° C. and was treated with sodium hexamethyldisilazide (353 μL, 0.353 mmol, 1 M in THF). The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was transferred to a separatory funnel containing saturated NaHCO₃ and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in hexanes→40% EtOAc in hexanes) to provide the target compound (22 mg, 17% yield) as a brown oil: ¹H NMR (CDCl₃) δ 6.72 (s, 2 H), 4.27 (t, J=7.88 Hz, 2 H), 4.00-3.95 (m, 1 H), 3.77 (s, 3 H), 3.09 (t, J=7.8 Hz, 2H), 2.48-2.38 (m, 2 H), 2.42 (s, 3 H), 1.95-1.81 (m, 2 H), 0.87 (t, J=7.5 Hz, 6 H); HRMS (ESI) m/z 396.1259 [(M+H)⁺, calcd for C₁₉H₂₄N₃O₂Cl₂ 396.1246].

Example 537 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-cyclobutylpropyl)-6-methyl-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 536 using 1-(1-cyclobutylpropyl)-3,5-dichloro-6-methyl-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials to give a yellow amorphous solid; ¹H NMR (300 MHz, CDCl₃) δ 6.73 (s, 2H), 4.28 (t, J=8.4 Hz, 2H), 4.04-3.97 (m, 1H), 3.79 (s, 3H), 3.62-3.55 (m, 1H), 3.10 (t, J=7.7 Hz, 2H), 2.50 (s, 3H), 2.42-2.35 (m, 1H), 2.22-2.10 (m, 1H), 1.90-1.50 (m, 5H), 1.58-1.50 (m, 1H), 0.86 (t, J=7.3 Hz, 3H); HRMS (ESI) m/z 422.1420 [(M+H)⁺, calcd for C₂₁H₂₆N₃O₂Cl₂ 422.1402].

Example 538 3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-methylpropyl-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-methylpropyl-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 150° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.32 (d, J=1.8 Hz, 1 H), 7.26 (d, J=1.9 Hz, 1 H), 6.85 (s, 1 H), 4.97-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 1.77-1.70 (m, 2 H), 1.36 (d, J=7.0 Hz, 3 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₆H₁₇N₃OBrCl₂ (M+H)⁺: 415.9932; Found m/z 415.9943.

Example 539 3-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-5-ethyl-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for XXXII (Example 481, part B) using 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) as the starting material and triethylaluminum in place of trimethylaluminum. mp 136-137° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.14 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.54 (s, 1 H), 4.90-4.79 (m, 1 H), 4.30 (t, J=8.1 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 2.44 (q, J=7.4 Hz, 2 H), 1.84-1.69 (m, 2 H), 1.67-1.61 (m, 2 H), 1.18 (t, J=7.5 Hz, 3 H), 0.86 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C₁₉H₂₄N₃OCl₂ (M+H)⁺: 380.1296; Found m/z 380.1280.

Example 540 3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 156-157° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=1.8 Hz, 1H), 7.19 (d, J=2.9 Hz, 1H), 6.71 (s, 1H), 4.75-4.69 (m, 1H), 4.27 (t, J=7.9 Hz, 2H), 3.07 (t, J=8.1 Hz, 2H), 1.78-1.51 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C₁₇H₁₉N₃OBrCl₂ (M+H)⁺: 430.0089; Found m/z 430.0106.

Example 541 6-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-4-(1-ethylpropyl)-4,5-dihydro-5-oxo-2-pyrazinecarbonitrile

A solution of 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) (100 mg, 0.23 mmol), zinc cyanide (32 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium(0) (32 mg, 25 μmol) in dimethylforamide (3 ml) was degassed with nitrogen and heated to 175° C. in a microwave for 5 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×2). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a crude residue. Purification by HPLC (reverse phase C18, 95% water in acetonitrile containing 0.1% trifluroacetic acid to 5% water in acetonitrile containing 0.1% trifluroacetic acid, flow rate 18 ml/min, retention time 38.4 min) gave the product (18 mg, 21%) as a yellow solid. mp 197-199° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.27 (s, 1 H), 7.19 (d, J=2.2 Hz, 1H), 7.14 (d, J=1.8 Hz, 1 H), 4.82-4.77 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.15 (t, J=7.7 Hz, 2 H), 1.92-1.78 (m, 2 H), 1.75-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C₁₈H₁₉N₄OCl₂ (M+H)⁺: 377.0936; Found m/z 377.0910.

Example 542 3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-[(1R)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 154-156° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.8 Hz, 1 H), 7.01 (s, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 4.05 (app. q, J=8.2 Hz, 1H), 3.14 (t, J=7.9 Hz, 2 H), 1.96-1.83 (m, 2 H), 1.07-1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81-0.75 (m, 1 H), 0.55-0.48 (m, 2 H), 0.35-0.28 (m, 1 H); HRMS (ESI) calcd for C₁₈H₁₉N₃OBrCl₂ (M+H)⁺: 442.0089; Found m/z 442.0102.

Example 543 3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 1-[(1S)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 126-127° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.4 Hz, 1 H), 7.01 (s, 1H), 4.32 (t, J=7.9 Hz, 2 H), 4.08-4.02 (m, 1 H), 3.14 (t, J=8.1 Hz, 2 H), 1.94-1.78 (m, 2 H), 1.05-1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81-0.77 (m, 1 H), 0.54-0.48 (m, 2 H), 0.34-0.30 (m, 1 H); HRMS (ESI) calcd for C₁₈H₁₉N₃OBrCl₂ (M+H)⁺: 442.0089; Found m/z 442.0093.

Example 544 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 126-128° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.99 (s, 1 H), 6.74 (s, 2 H), 5.00-4.90 (m, 1 H), 4.35 (t, J=8.0 Hz, 2 H), 3.78 (s, 3H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.09 (t, J=7.7 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C₁₈H₂₂N₃O₃Cl₂ (M+H)⁺: 398.1038; Found m/z 398.1064.

Example 545 5-Chloro-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1 H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 62-64° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.92 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 5.02-4.92 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.3, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.90-1.70 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₉H₂₅N₃O₃Cl (M+H)⁺: 378.1584; Found m/z 378.1604.

Example 546 1-[6-Chloro-4-[(1R)-1-(methoxymethyl)propyl]-3,4-dihydro-3-oxopyrazinyl]-5-methoxy-2,3-dihydro-1H-indole-7-carbonitrile

Prepared in a similar fashion as described for Example 541 using 3-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone (Example 523) as the starting material. mp 141-142° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.11 (s, 1 H), 6.99 (d, J=2.6 Hz, 1 H), 6.87 (d, J=2.6 Hz, 1 H), 5.00-4.90 (m, 1H), 4.41 (t, J=8.1 Hz, 2 H), 3.79 (s, 3 H), 3.68 (dd, J=10.7, 5.2 Hz, 1 H), 3.59 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.95-1.75 (m, 2 H), 0.95 (t, J=7.3 Hz, 3 H); HRMS (CI) calcd for C₁₉H₂₁N₄O₃Cl (M+H)⁺: 388.1302; Found m/z 388.1298.

Example 547 5-Bromo-3-(5-bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 118° C.; ¹H NMR (300 MHz, CDCl₃): δ 7.31 (s, 1 H), 7.24 (s, 1 H), 7.13 (s, 1 H), 4.98-4.90 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.66 (dd, J=10.7, 5.9 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.13 (t, J=7.9 Hz, 2 H), 1.85-1.74 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂Br₂Cl (M+H)⁺: 489.0543; Found m/z 489.9534.

Example 548 3-(5-Bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 121-122° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.24 (s, 1 H), 7.18 (s, 1 H), 6.99 (s, 1 H), 4.90-4.80 (m, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.60 (dd, J=10.2, 5.5 Hz, 1 H), 3.49 (dd, J=10.6, 3.3 Hz, 1 H), 3.28 (s, 3 H), 3.06 (t, J=8.1 Hz, 2 H), 1.83-1.65 (m, 2H), 0.86 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C₁₇H₁₉N₃O₂BrCl₂ (M+H)⁺: 446.0038; Found m/z 446.0048.

Example 549 5-Bromo-3-(5-methoxy-7-methyl-2,3-dihydro-1H-indol-1-yl)-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 115-117° C.; ¹H NMR (300 MHz, CDCl₃): δ 6.98 (s, 1 H), 6.66 (m, 1 H), 6.58 (d, J=2.2 Hz, 1 H), 5.00-4.90 (m, 1 H), 4.38 (t, J=8.1 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.2, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.92-1.70 (m, 2 H), 0.94 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C₁₉H₂₅N₃O₃Br (M+H)⁺: 422.1079; Found m/z 422.1096.

Example 550 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

Part A: A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (6.19 g, 37.9 mmol) in CH₂Cl₂ (76 mL) was treated with pyridinium tribromide (25.42 g, 79.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with sat NaHSO₃ (50 mL) and water (50 mL). The dichloromethane was separated, dried (Na₂SO₄) and concentrated. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline (2.93 g, 32% yield): ¹H NMR (300 MHz, CDCl₃): δ 6.88 (s 1 H), 6.55 (s, 1 H), 3.71 (s, 3H), 3.37-3.33 (t, J=6.6, 2 H), 2.78-2.74 (t, 2 H), 1.97-1.89 (m, 2 H); LRMS (AP⁺) for (M+H)⁺: for C₁₀H₁₂NOBr Calculated: 241.1 found: 241.0.

Part B: Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 125-126° C.; HRMS (ESI) calcd for C₁₉H₂₄N₃O₂BrCl (M+H)⁺: 440.0740; Found m/z 440.0750.

Example 551 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1 H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 127-129° C.; HRMS (ESI) calcd for C₂₀H₂₄N₃O₂BrCl (M+H)⁺: 452.0740; Found m/z 452.0766.

Example 552 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 118-119° C.; HRMS (ESI) calcd for C₂₀H₂₄N₃O₂BrCl (M+H)⁺: 452.0740; Found m/z 452.0734.

Example 553 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 146° C.; HRMS (ESI) calcd for C₁₈H₂₂N₃O₃BrCl (M+H)⁺: 442.0533; Found m/z 442.0557.

Example 554 5-Bromo-3-(8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 102-103° C.; HRMS (ESI) calcd for C₁₉H₂₄N₃O₃Br₂ (M+H)⁺: 500.0185; Found m/z 500.0205.

Example 555 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline as the starting materials. mp 93-94° C.; HRMS (ESI) calcd for C₁₉H₂₄N₃O₃BrCl (M+H)⁺: 456.0690; Found m/z 456.0670.

Example 556 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Synthesis of intermediate 5-Bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine

Part A: 5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25% w/w solution in MeOH). The reaction mixture was heated at 60° C. for 40 h. The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93% yield) as a yellow solid: mp 93.0-94.0° C., ¹H NMR (300 MHz, CDCl₃): δ 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).

Part B: The product from Part A (3.0 g, 17.7 mmol) was dissolved in methanol (120 mL). The reaction vessel was evacuated and flushed with nitrogen and 10% Pd/C (600 mg) was added. The mixture was placed under an H₂ atmosphere on the Parr shaker for 1 h. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to give 2-amino-5-methoxyphenol (2.52 g, 100% yield) as a brown solid which was used directly in the next step without further purification: ¹H NMR (300 MHz, CDCl₃): δ 6.78 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.9 Hz, 1H), 6.35 (dd, J=8.4, 2.9 Hz, 1H), 3.73 (s, 3H).

Part C: To a vigorously stirred solution of the product from Part B (12.34 g, 88.69 mmol) in dry acetone (355 mL) was added K₂CO₃ (9.00 g, 68.70 mmol) followed by the addition of 1,2-dibromoethane (2.50 mL, 28.75 mmol). Three additional portions of K₂CO₃ (9.00 g, 68.70 mmol) and 1,2-dibromoethane (2.50 mL, 28.75 mmol) were added at 30 min intervals. The reaction mixture was then heated at reflux overnight. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated and purified by column chromatography on silica gel (10% EtOAc.40% EtOAc in hexanes) to furnish 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine (4.60 g, 31% yield) as a yellow oil and recovered starting material (2.5 g, 20% recovery): ¹H NMR (300 MHz, CDCl₃): δ 6.55 (d, J=8.5 Hz, 1H), 6.42-6.35 (m, 2H), 4.25-4.21 (m, 2H), 3.72 (s, 3H), 3.38-3.35 (m, 2H); LRMS (APCI) m/z 166.0 [(M+H)⁺, calcd for C₉H₁₂NO₂ 166.2].

Part D: A mixture of the product from Part C (4.60 g, 27.85 mmol) and pyridinium tribromide (9.80 g, 30.63 mmol) in CH₂Cl₂ (280 mL) was stirred at room temperature for 6.5 h. The reaction mixture was quenched with saturated aqueous Na₂SO₃. The aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were washed with H₂O, brine, dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc.30% EtOAc in hexanes) to afford 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine (1.34 g, 20% yield) as a pale yellow oil: ¹H NMR (300 MHz, CDCl₃): δ 6.65 (d, J=3.0 Hz, 1H), 6.40 (d, J=2.9 Hz, 1H), 4.25-4.22 (m, 2H), 3.71 (s, 3H), 3.46-3.42 (m, 2H).

Synthesis of Example 556

3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone (67.9 mg, 0.275 mmol) and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine (67 mg, 0.275 mmol) were combined in THF (1.4 mL). The mixture was cooled to 0° C. and was treated with NaHMDS (302 μL, 0.302 mmol, 1 M in THF). The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing saturated NaHCO₃ and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc→30% EtOAc in hexanes) to afford a brown oil. ¹H NMR (300 MHz, CDCl₃): δ 6.73 (d, J=1.5 Hz, 1H), 6.70 (s, 1H), 6.45 (d, J=1.3 Hz, 1H), 4.31-4.00 (m, 5H), 3.75 (s, 3H), 1.89-1.74 (m, 2H), 1.05-1.02 (m, 1H), 0.93 (t, J=7.3 Hz, 3H), 0.90-0.75 (m, 1H), 0.52-0.49 (m, 2H), 0.35-0.25 (m, 1H); HRMS (ESI) m/z 453.0459 [M⁺, calcd for C₁₉H₂₁N₃O₃BrCl 453.0455].

Example 557 5-Chloro-3-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials to give a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 6.74 (s, 2H), 6.67 (s, 1H), 4.90-4.80 (m, 1H), 4.34 (t, J=7.9 Hz, 2H), 3.78 (s, 3H), 3.10 (t, J=7.7 Hz, 2H), 2.60-2.50 (m, 1H), 2.18-2.12 (m, 1H), 1.90-1.70 (m, 6H), 1.55-1.43 (m, 1H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 408.1270 [(M+H)⁺, calcd for C₂₀H₂₄N₃O₂Cl₂ 408.1246].

Example 558 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinoneand 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 6.73 (d, J=2.9 Hz, 1H), 6.72 (s, 1H), 6.45 (d, J=2.6 Hz, 1H), 4.90-4.85 (m, 1H), 4.50-3.88 (m, 4H), 3.76 (s, 3H), 2.58-2.50 (m, 1H), 2.18-2.13 (m, 1H), 1.85-1.65 (m, 6H), 1.50-1.40 (m, 1H), 0.83 (t, J=7.4 Hz, 3H); HRMS (ESI) m/z 468.0665 [M⁺, calcd for C₂₀H₂₄N₃O₃BrCl 468.0690].

Example 559 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 5-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 6.70 (s, 1H), 6.55 (d, J=2.9 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 4.88 (s br, 1H), 4.40-4.00 (m, 4H), 3.76 (s, 3H), 2.60-2.45 (m, 1H), 2.18-2.12 (m, 1H), 1.96-1.60 (m, 6H), 1.56-1.36 (m, 1H), 0.83 (t, J=7.6 Hz, 3H); HRMS (ESI) m/z 424.1199 [(M+H)⁺, calcd for C₂₀H₂₄N₃O₃Cl₂ 424.1195].

Example 560 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.03 (s, 1H), 6.73 (d, J=2.9 Hz, 1H), 6.45 (d, J=2.9 Hz, 1H), 4.44-3.89 (m, 5H), 3.75 (s, 3H), 1.96-1.70 (m, 2H), 1.12-1.00 (m, 1H), 0.92 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.84-0.72 (m, 1H), 0.56-0.44 (m, 2H), 0.35-0.25 (m, 1H); HRMS (ESI) m/z 454.0518 [(M+H)⁺, calcd for C₁₉H₂₂N₃O₃BrCl 454.0533].

Example 561 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1R)-(1-methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.05 (s, 1H), 6.73 (d, J=2.5 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.09-4.86 (m, 1H), 4.50-3.84 (m, 4H), 3.76 (s, 3H), 3.70-3.52 (m, 2H), 3.34 (s, 3H), 1.92-0.76 (m, 5H); HRMS (ESI) m/z 457.0410 [M⁺, calcd for C₁₈H₂₁N₃O₄BrCl 457.0404].

Example 562 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-(1-methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.05 (s, 1H), 6.73 (d, J=2.9 Hz, 1H), 6.45 (d, J=2.9 Hz, 1H), 5.08-4.86 (m, 1H), 4.52-3.84 (m, 4H), 3.76 (m, 3H), 3.68-3.52 (m, 2H), 3.34 (m, 3H), 2.00-0.80 (m, 5H); HRMS (ESI) m/z 458.0457 [(M+H)⁺, calcd for C₁₈H₂₂N₃O₄BrCl 458.0482].

Example 563 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-chloro-1-[(1S)-2-methoxy-1-methylethyl]-2(1H)-pyrazino

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.06 (s, 1H), 6.74 (d, J=3.0 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.24-5.10 (m, 1H), 4.52-3.86 (m, 4H), 3.76 (s, 3H), 3.57 (d, J=3.7 Hz, 2H), 3.35 (s, 3H), 1.41 (d, J=6.9 Hz, 3H); HRMS (ESI) m/z 444.0339 [(M+H)⁺, calcd for C₁₇H₂₀N₃O₄BrCl 444.0326].

Example 564 5-chloro-1-(1-cyclobutylpropyl)-3-(7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example aaa using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 6.91 (d, J=9.5 Hz, 1H), 6.69 (s, 1H), 6.46-6.41 (m, 2H), 4.92-4.82 (m, 1H), 4.34-4.31 (m, 2H), 4.20-4.16 (m, 2H), 3.76 (s, 3H), 2.64-2.50 (m, 1H), 2.24-2.12 (m, 1H), 1.96-1.40 (m, 7H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 390.1595 [(M+H)⁺, calcd for C₂₀H₂₅N₃O₃Cl 390.1584].

Example 565 5-chloro-1-[(1R)-1-cyclopropylpropyl]-3-(7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 6.98 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 6.44-6.41 (m, 2H), 4.33-4.30 (m, 2H), 4.18-4.08 (m, 3H), 3.75 (s, 3H), 1.92-1.78 (m, 2H), 1.10-1.00 (m, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.81-0.77 (m, 1H), 0.60-0.48 (m, 2H), 0.38-0.20 (m, 1H); HRMS (ESI) m/z 376.1452 [(M+H)⁺, calcd for C₁₉H₂₃N₃O₃Cl 376.1428].

Example 566 3-(5-Bromo-7-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5-bromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Prepared in a similar fashion as described for Example 556 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.14 (s, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.08-4.86 (m, 1H), 4.50-3.88 (m, 4H), 3.77 (s, 3H), 3.70-3.52 (m, 2H), 3.36 (s, 3H), 1.92-1.70 (m, 2H), 0.93 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 501.9992 [(M+H)⁺, calcd for C₁₈H₂₂N₃O₄Br₂ 501.9977].

Utility

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity.

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in a standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 ‘t’ splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10⁻¹⁰-10⁻⁵ M), 100 μl of ¹²⁵I-ovine-CRF (¹²⁵I-o-CRF) (final concentration 150 pM) and 150 μl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of CRF. Preferred compounds have a K_(i) value of less than about 1000 nM for the inhibition of CRF. More preferred compounds have a K_(i) value of less than about 100 nM for the inhibition of CRF.

Compounds of the present invention have demonstrated a K_(i) value of less than about 10000 nM for the inhibition of CRF in the CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity.

Alternate CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity.

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in a standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 ‘t’ splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below.

HEK 293 EBNA-1 cells (HEK 293E, Invitrogen, CA), were transfected with a vector encoding the human CRF-R1 gene using a standard calcium phosphate protocol. The vector sequence included the oriP origin of replication, which permits episomal maintenance in cells expressing the EBNA-1 gene, and the gene for hygromycin resistance. Following transfection, cells were pooled and plated into a medium containing hygromycin for the selection of cells expressing CRF-R1. After isolation, the cell pool CL0138 was assessed in radioligand binding and functional-based assays. These cells are maintained in Dulbecco's Modified Eagle medium (DMEM) containing 10% v/v fetal bovine serum (FBS), 2 mM L-glutamine and 400 μg/mL hygromycin. Cell pellets prepared from this cell line were used in CRF₁ competition binding assays. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet, frozen and stored at −80° C.

A frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors or the rat frontal cortex tissue dissected from frozen rat brains was prepared as the source of membranes expressing CRF1 receptors used in binding assays. Tissue or pellets of whole cells were thawed on ice and homogenized in tissue buffer (containing 50 mM HEPES, 10 mM MgCl₂, 2 mM EGTA, and 1 μg/mL each of aprotonin, leupeptin, and pepstatin, pH 7.0 @ 23° C.) using a Brinkman Polytron (PT-10, setting 6 for 10 seconds). The homogenate was centrifuged at 48,000×g for 12 min and the resulting pellet was washed by a single re-suspension and centrifugation step. Membranes from rat frontal cortex were prepared similarly except for the inclusion of an additional wash/centrifugation cycle. The final pellet was suspended in tissue buffer, and protein concentrations were determined using the bicinchoninic acid (BCA) assay (Pierce, Rockford, Ill.) with bovine serum albumin as standard.

Equilibrium competition binding experiments were performed using a modification of the methods described previously to determine binding affinities of compounds at CRF₁ receptors (Arvantis et al., 1999; Rominger et al., 1998). All small molecule ligands were initially prepared in 100% DMSO at a concentration of 10⁻² M and diluted in assay buffer that was identical to the tissue buffer except for the inclusion of 0.15 mM bacitracin and 0.1% w/v ovalbumin. Competition assays were conducted in disposable polypropylene 96-well plates in a total volume of 300 μL. The reaction was initiated by the addition of 50 μL competing compounds in 12 concentrations (final concentrations ranging from 10-¹¹ to 10-⁵ M), 100 μL assay buffer containing the radioligand [¹²⁵I]ovine CRF (final concentration 150 pM), and 150 μL membrane homogenate (containing 5-10 μg protein). The reaction mixtures were incubated to equilibrium for 2 h at 23° C. Specific binding was defined in the presence of 10 μM DMP 696 or SC241 for CRF₁ receptors. Competition binding assays were terminated by rapid filtration over GF/C glass-fibers (pre-soaked in 0.3% v/v polyethyleneimine) using a 96-well cell harvester followed by two-three washes with 0.3 mL cold wash buffer (PBS, pH 7.0, containing 0.01% Triton X-100). The filter was dried, and counted in a gamma counter or a 96-well Packard Top Counter at 80% efficiency. The CRF₁ competition binding to membranes from rat frontal cortex were performed similarly except for the radioligand concentration of [¹²⁵I]ovine CRF (final concentration approximately 200 pM) and membrane protein (40-65 μg/well) used in the binding.

The inhibition of [¹²⁵I]ovine CRF binding to cell membranes by increasing concentrations of test drugs are analyzed by fitting data through the competition equation in the iterative nonlinear regression curve-fitting programs Prism (GraphPad Prism, San Diego, Calif.) to determine binding affinities (IC₅₀ 's or Ki's) of ligands for CRF₁ receptors. A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of [¹²⁵I]ovine CRF binding.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10^(−6m)) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/³²P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990).

Compounds may be tested in any species of rodent or small mammal.

Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences”, A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims. 

1. A compound of Formula (I-d):

or a pharmaceutically acceptable salt form thereof, wherein: R¹ is H, F, Cl, Br, —CN, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl; R³ is C₁-C₆ alkyl optionally substituted with 1 or 2 substituents independently selected at each occurrence from the group consisting of methyl, ethyl, methoxy, ethoxy, methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, and —CF₃; R⁴ is —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; and R⁵ is independently at each occurrence —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.
 2. A compound of claim 1 of Formula (I-d):

or a pharmaceutically acceptable salt form thereof, wherein: R¹ is H, F, Cl, Br, methyl, ethyl, —CN, or —CF₃; R³ is butyl-, pentyl-, hexyl-, heptyl-, methoxy-ethyl-, methoxy-propyl-, methoxy-butyl-, methoxy-pentyl-, methoxy-hexyl-, methylthio-ethyl-, methylthio-propyl-, methylthio-butyl-, methylthio-pentyl-, methylthio-hexyl-, 1-cyclopropyl-propyl-, 1-cyclopropyl-butyl-, 1-cyclopropyl-pentyl-, 1-cyclobutyl-propyl-, 1-cyclobutyl-butyl-, 1-cyclobutyl-pentyl, 1-cyclopropyl-1-(CF₃)-methyl-, 1-cyclopropyl-2-(CF₃)-ethyl-, 1-cyclopropyl-3-(CF₃)-propyl-, 1-cyclobutyl-1-(CF₃)-methyl-, 1-cyclobutyl-2-(CF₃)-ethyl-, or 1-cyclobutyl-3-(CF₃)-propyl-; R⁴ is H, methyl-, ethyl-, methoxy-, ethoxy-, isopropoxy-, n-propoxy-, F, Cl, Br, —CF₃, —OCF₃, —OCHF₂, or —CN; and R⁵ is independently at each occurrence, —H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br, or —CF₃.
 3. A compound of claim 1 that is: 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone; 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone; 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone; 5-Bromo-3-(8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; or 3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone.
 4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
 5. A method of treating a mammal afflicted with anxiety or depression which method comprises administering to the mammal a dose of the pharmaceutical composition of claim
 4. 6. The method of claim 5 wherein the mammal is afflicted with anxiety.
 7. The method of claim 5 wherein the mammal is afflicted with depression. 